Methods of treating tumor metastasis

ABSTRACT

The present invention provides methods for treating or suppressing tumor metastasis at a site distinct from the bladder in an individual having a urothelial carcinoma of lower tract, comprising locally delivering to the bladder an effective amount of a chemotherapeutic agent (such as gemcitabine), wherein the chemotherapeutic agent is delivered continuously to the bladder for a sustained period of time (such as at least 24 hours).

CROSS-REFERENCE TO RELATED APPLICATION

This application claims priority benefit of U.S. Provisional ApplicationNo. 62/536,949, filed on Jul. 25, 2017, entitled “METHODS OF TREATINGTUMOR METASTASIS,” the contents of which this incorporated herein byreference in its entirety.

TECHNICAL FIELD

The present invention relates to methods of treating tumors or tumormetastasis at a distant site, by continuously delivering to the bladderan effective amount of a chemotherapeutic agent.

BACKGROUND

Cancerous diseases and tumors in general are among the major causes forhuman deaths and severe illness. Tumor metastasis is a major contributorto the deaths of cancer patients. Even after surgical removal of atumor, patients frequently suffer from cancer, mostly from tumormetastasis.

Metastatic cancer is especially difficult to treat because themetastatic tumor cells can adapt quickly and become resistant totreatment. Typically, metastatic cancer requires systemic therapy toreach cancer cells throughout the body, such as chemotherapy or hormonetherapy. Effectiveness of these therapies depends on various factorssuch as the type of the specific cancer and specific patient population.In general, effectiveness of currently available therapies formetastatic cancer is far from ideal because of the poor effectivenessand serious and/or unnecessary damage to the human body.

Bladder cancer is a significant medical problem, and currently availabletreatment options are unsatisfactory for a number of reasons. Ingeneral, bladder cancers are classified as muscle invasive bladdercancer (MIBC) or non-muscle invasive bladder cancer (NMIBC). Thepathological classification and staging of bladder cancer is as follows:pTa (urothelial involvement); pTis (high risk urothelial confined); pT1(lamina propria invasion); pT2 (muscularis invasion); pT3 (perivesicalfat invasion); and pT4 (pelvic organ extension). Bladder cancers canalso be classified by grade as Grade 1/3 (well differentiated); Grade2/3 (moderately differentiated); and Grade 3/3 (poorly differentiated).Recently the World Health Organization recommended using a two scalegrading system for bladder cancer, low grade and high grade. Inaddition, bladder cancers can be classified by stage as Stages 0-IV.Most bladder cancers are transitional cell carcinomas of epithelialorigin and classified as non-muscle invasive bladder cancer (NMIBC)confined to the inner lining of the bladder. At initial presentation,most bladder cancers are superficial NMIBCs and include stages pTa, pTisand pT1 disease. Muscle invasive bladder cancer (MIBC) includes stagespT2, pT3 and pT4.

The typical clinical approach used to treat early stage NMIBC iscystoscopic visualization followed by surgical removal of the tumor(s),known as transurethral resection (TUR). However, there is a high rate ofrecurrence after surgery and the cancer may progress to muscle-invasivedisease. Therefore, surgery is often combined with adjuvant intravesicalinstillation (direct delivery of the chemotherapeutic agent into thebladder through a urinary catheter for a brief period of time usuallyless than 1 hour) of chemotherapeutic or immunotherapeutic agents tohelp suppress or delay the recurrence. Bacillus Calmette-Guerin (BCG) issuch an immunotherapeutic and is instilled into the bladder followingsurgery for higher grades of non-muscle invasive bladder cancer (NMIBC).However, many patients do not respond to BCG, and BCG treatment can alsoinduce a range of adverse effects leading to discontinuation oftreatment. Chemotherapeutic agents are usually reserved for patients whohave failed BCG therapy. Chemotherapy is typically appliedintravesically to concentrate the chemotherapeutic agent at the tumorsites to help eliminate any residual tumor after resection whilereducing systemic exposure of the drug.

Muscle invasive bladder cancer is generally more likely to metastasizecompared to non-muscle invasive bladder cancer. Accordingly, patientswith muscle invasive bladder cancer typically receive cisplatin-basedneoadjuvant chemotherapy followed by radical cystectomy, or removal ofthe bladder. On the other hand, patients with muscle-invasive bladdercancer who are medically unfit, or elect not to have a radicalcystectomy typically receive maximal transurethral resection of bladdertumors (TURBT) in combination with chemotherapy.

One such chemotherapeutic agent used in clinical trials for treatingbladder cancer is gemcitabine. Gemcitabine (2′,2′-difluorodeoxycytidine)is a pyrimidine analogue with activity against metastatic bladdercancer. Gemcitabine has also been used in clinical trials to treat NMIBCby instillation in the bladder with various weekly schedules.Gemcitabine is typically instilled over 1 to 2 hours once or twice aweek for several weeks at doses typically ranging from 500 to 2000 mg inup to 100 mL of saline.

It is known that such liquid formulations are voided from the bladderafter short dwell times of 1 to 2 hours thus limiting their therapeuticbenefit. In addition, high concentrations (40 mg/mL) and high doses (upto 2 grams per instillation) are used in an attempt to achievetherapeutic tissue levels with limited dwell time. However, in additionto local tolerability issues, intravesical delivery of high doses ofgemcitabine can lead to significant systemic absorption and causegastrointestinal, bladder and bone marrow toxicity further limiting itsutility.

Systemic gemcitabine is often used in combination with systemiccisplatin both neoadjuvantly and adjuvantly to radical cystectomy totreat muscle invasive bladder cancer and to treat metastatic disease.However, many patients are ineligible or refuse treatment with theseagents due to their side effects which include bone marrow suppression.

Accordingly, there remains a need for methods for treating tumors atdistant sites in an individual with a tumor in the bladder.

The disclosures of all publications, patents, patent applications andpublished patent applications referred to herein are hereby incorporatedherein by reference in their entirety.

BRIEF DESCRIPTION

The present invention in various aspects provides methods of treatingtumor metastasis, reducing (such as eradicating) preexisting tumormetastasis, reducing incidence or burden of preexisting tumormetastasis, suppressing or delaying tumor metastasis, inhibiting tumorcells at a second site distinct from a first tumor site in the bladderof an individual comprising locally delivering to the bladder aneffective amount of a chemotherapeutic agent, wherein thechemotherapeutic agent is delivered continuously to the bladder forperiod of time.

In some embodiments, there is provided a method of inhibiting tumor cellgrowth at a second tumor site distinct from a first tumor site in thebladder of an individual, comprising locally delivering to the bladderan effective amount of a chemotherapeutic agent, wherein thechemotherapeutic agent is delivered continuously to the bladder for atleast about 24 hours. In some embodiments, the tumor cells at the secondtumor site are located at a pelvic node. In some embodiments, the tumorcells at the second tumor site are located at a distant node. In someembodiments, the tumor cells at the second tumor site are circulatingtumor cells. In some embodiments, the tumor cells at the first tumorsite result from metastasis of a primary tumor at the second tumor site.In some embodiments, the tumor cells at the second site are selectedfrom the group consisting of liver, lung, bone, brain, lymph node,pelvic node, peritoneum, skin, prostate, breast, colon, rectum, andcervix. In some embodiments, the individual has a urothelial carcinomaof lower tract.

In some embodiments, also provided herein is a method of treating orsuppressing tumor metastasis at a site distinct from the bladder in anindividual having a urothelial carcinoma of lower tract, comprisinglocally delivering to the bladder an effective amount of achemotherapeutic agent, wherein the chemotherapeutic agent is deliveredcontinuously to the bladder for at least about 24 hours. In someembodiments, the tumor metastatic site is at one or more of: liver,lung, bone, brain, lymph node, pelvic node, peritoneum, skin, prostate,breast, colon, rectum, and cervix. In some embodiments, the tumormetastasis is at two or more different sites.

In some embodiments according to any of the methods described above, theindividual has bladder cancer. In some embodiments, the individual hasmuscle invasive bladder cancer or carcinoma in situ (CIS). In someembodiments, the individual is unfit for or refuses cystectomy.

In some embodiments according to any of the methods described above, theindividual has not undergone transurethral resection of bladder tumors(TURBT).

In other embodiments, the individual has undergone transurethralresection of bladder tumors (TURBT). In some of these embodiments, theindividual has undergone transurethral resection of bladder tumors(TURBT) and has residual tumor at the site of resection.

In some embodiments according to any of the methods described above, thechemotherapeutic agent is delivered at a dose of from about 1 mg/day toabout 300 mg/day. In some embodiments, the concentration of thechemotherapeutic agent in the urine is from about 0.1 μg/mL to about 200μg/mL during the delivery period.

In some embodiments according to any of the methods described above, thechemotherapeutic agent is delivered continuously to the bladder of theindividual for a period of about 7 days to about three weeks. In someembodiments, the method comprises an induction delivery period followedby a maintenance delivery period. In some embodiments, the inductiondelivery period and the maintenance delivery period are separated by arest period of about 7 to about 14 days. In some embodiments, thechemotherapeutic agent is delivered at a first release rate during theinduction delivery period followed and a second release rate during themaintenance delivery period.

In some embodiments according to any of the methods described above, themethod comprises a) an induction delivery period, wherein theconcentration of chemotherapeutic agent in the urine of the individualis at least about 0.1 μg/mL; b) a rest period; and c) a maintenancedelivery period, wherein the concentration of the chemotherapeutic agentin the urine of the individual is greater than about 0.1 μg/mL.

In some embodiments according to any of the methods described above, theindividual does not receive a radiation therapy. In other embodiments,the method further comprises a radiation therapy.

In some embodiments according to any of the methods described above, thechemotherapeutic agent is delivered by an intravesical delivery device.In some embodiments, the intravesical device contains 100 mg to 500 mgof the chemotherapeutic agent. In some embodiments, the intravesicaldevice comprises a housing configured for intravesical insertion; and adosage form comprising chemotherapeutic agent, wherein the housing holdsthe dosage form and is configured to release chemotherapeutic agent. Insome embodiments, the intravesical drug delivery device comprises: ahousing defining a reservoir; a first unit contained within thereservoir, the first unit comprising an chemotherapeutic agent; and asecond unit contained within the reservoir in a position distinct fromthe first unit, wherein the second unit comprises a functional agentthat facilitates in vivo release of the chemotherapeutic agent from thehousing. In some embodiments, the intravesical drug delivery devicecomprises a housing which contains and controllably releases thechemotherapeutic agent and is elastically deformable between a retentionshape configured to retain the device in the individual's bladder and adeployment shape for passage of the device through the individual'surethra. In some embodiments, the device comprises a drug reservoirlumen bounded by a first wall and a second wall, wherein the first wallis impermeable to the drug and the second wall is permeable to thechemotherapeutic agent. In some embodiment, the chemotherapeutic agentis released from the device by osmotic pressure. In some embodiments,the chemotherapeutic agent is released from the device by diffusion. Insome embodiment, the chemotherapeutic agent contained in the housing isin a non-liquid form. In some embodiments, the non-liquid form isselected from the group consisting of tablets, granules, powders,semisolids, capsules, and combinations thereof.

In some embodiments according to any of the methods described above, thechemotherapeutic agent is selected from the group consisting of anucleoside analog, a taxane, a platinum-based agent, and ananthracycline analogue. In some embodiments, the chemotherapeutic agentis a nucleoside analog. In some of these embodiments, the nucleosideanalog is gemcitabine.

In some embodiments according to any of the methods described above, theindividual is human. In some embodiments, the individual is unsuitablefor systemic chemotherapy. In some embodiments, the individual has acompromised immune system. In some embodiments, the individual has ahigh tumor burden.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a modified bladder perfusion system to introduce tumorsinto bladder and subcutaneous tissue.

FIG. 2 shows the treatment and dosing schedule for four groups ofrats: 1) untreated rats inoculated with subcutaneous tumor only; 2)untreated rats inoculated with bladder tumor and then subcutaneoustumor; 3) rats inoculated with bladder tumor, perfused with 180 μg/mLgemcitabine, and then inoculated with subcutaneous tumor and againperfused with 180 μg/mL gemcitabine; and 4) rats inoculated with bladdertumor and subcutaneous tumor simultaneously and perfused with 180 μg/mLgemcitabine twice.

FIG. 3 shows the average volume of subcutaneous tumors in four groups ofrats after introducing tumors into bladder and/or subcutaneous tissueand during the course of the treatment.

FIG. 4 shows the volume of subcutaneous tumors in each individual rat inthe four groups after introducing tumors into bladder and/orsubcutaneous tissue and during the course of the treatment.

FIGS. 5A-5C show an intravesical device that can be used to providelocal and continuous delivery of a chemotherapeutic agent. FIG. 5A is aplan view. FIG. 5B is a cross-sectional view taken along line 3-3 inFIG. 5A. FIG. 5C is a view of one end portion of the device disposedwithin the working channel of a deployment instrument, which is shown inpartial cross-section.

FIG. 6 shows the mean tumor volume of subcutaneous tumors in rats withbladder tumors treated with vehicle or gemcitabine perfusionconcentrations of 45 μg/ml and 90 μg/ml, producing nominal urineconcentrations of 10 μg/ml and 20 μg/ml.

FIG. 7 shows the mean tumor volume of subcutaneous tumors in ratswithout bladder tumors treated with vehicle or gemcitabine perfusionconcentrations of 45 μg/ml and 90 μg/ml, producing nominal urineconcentrations of 10 μg/ml and 20 μg/ml.

FIG. 8 shows circulating TGF-β levels in rats inoculated with NBT-IIbladder tumor cells, either without gemcitabine treatment (NBT-II) orupon intravesicular treatment with gemcitabine (GEM).

FIG. 9 shows circulating IL-10 levels in rats inoculated with NBT-IIbladder tumor cells, either without gemcitabine treatment (NBT-II) orupon intravesicular treatment with gemcitabine (GEM).

FIG. 10 shows circulating TNF-α levels in rats inoculated with NBT-IIbladder tumor cells, either without gemcitabine treatment (NBT-II) orupon intravesicular treatment with gemcitabine (GEM).

FIG. 11 shows activated CD4 and CD8 splenic T cell populations in tumorbearing rats administered intravesicular gemcitabine.

FIG. 12 shows FOXP3 splenic regulatory cell populations in tumor bearingrats administered intravesicular gemcitabine.

DETAILED DESCRIPTION

The present application provides methods for treating or suppressingtumor metastasis at a site distinct from the bladder in an individualhaving bladder cancer, comprising locally delivering (such asintravesical) to the bladder an effective amount of a chemotherapeuticagent (such as gemcitabine). The application is based in part on thesurprising finding that continuous delivery of gemcitabine to thebladder for a prolonged period of time has an extraordinary antitumoreffect at a tumor site distinct from the bladder. The effect is evenmore pronounced when the gemcitabine is continuously delivered more thanonce. Therefore, continuous delivery of a chemotherapeutic agent (suchas gemcitabine), especially a repeated local and continuous delivery ofthe chemotherapeutic agent (such as gemcitabine) to the bladder, asdescribed herein, can be a robust method to treat or suppress tumormetastasis or treat non-bladder tumors, wherein the bladder is a primarytumor site or secondary or metastatic site.

Thus, the present invention in various aspects provides methods oftreating tumor metastasis, reducing (such as eradicating) preexistingtumor metastasis, reducing incidence or burden of preexisting tumormetastasis, suppressing or delaying tumor metastasis, inhibiting tumorcells at a second site distinct from a first tumor site in the bladderof an individual comprising locally delivering to the bladder aneffective amount of a chemotherapeutic agent, wherein thechemotherapeutic agent is delivered continuously to the bladder forperiod of time. In one aspect, there is provided a method of inhibitingtumor cell growth at a second tumor site distinct from a first tumorsite in the bladder of an individual, comprising locally delivering tothe bladder an effective amount of a chemotherapeutic agent, wherein thechemotherapeutic agent is delivered continuously to the bladder for atleast about 24 hours. In another aspect, there is provided a method oftreating or suppressing tumor metastasis at a site distinct from thebladder in an individual having a urothelial carcinoma of lower tract,comprising locally delivering to the bladder an effective amount of achemotherapeutic agent, wherein the chemotherapeutic agent is deliveredcontinuously to the bladder for at least about 24 hours. Also providedare kits for carrying out any methods described herein.

Definitions

As used herein, the singular forms “a,” “an,” and “the” include pluralreferents unless the context clearly dictates otherwise. For example,“a” or “an” means “at least one” or “one or more.”

The term “continuous” or “continuously” as used herein refers tosustained administration of a chemotherapeutic agent (for examplegemcitabine) over a sustained period of time.

The term “individual” as used herein refers to a mammal, includinghumans. An individual includes, but is not limited to, human, bovine,horse, feline, canine, rodent, or primate. In some embodiments, theindividual is human.

Reference to “about” a value or parameter herein includes (anddescribes) embodiments that are directed to that value or parameter perse. For example, “about 7 days” includes 7 days.

The term “about X-Y” used herein has the same meaning as “about X toabout Y.”

The methods may be practiced in an adjuvant setting. “Adjuvant setting”refers to a clinical setting in which an individual has had a history ofa proliferative disease, particularly cancer, and generally (but notnecessarily) been responsive to therapy, which includes, but is notlimited to, surgery (such as surgical resection), radiotherapy, andchemotherapy. However, because of their history of the proliferativedisease (such as cancer), these individuals are considered at risk ofdevelopment/progression of the disease. Treatment or administration inthe “adjuvant setting” refers to a subsequent mode of treatment. Thedegree of risk (i.e., when an individual in the adjuvant setting isconsidered as “high risk” or “low risk”) depends upon several factors,most usually the extent of disease when first treated. The methodsprovided herein may also be practiced in a neoadjuvant setting, i.e.,the method may be carried out before the primary/definitive therapy. Insome embodiments, the individual has previously been treated. In someembodiments, the individual has not previously been treated. In someembodiments, the treatment is a first line therapy.

As used herein, “treatment” or “treating” is an approach for obtainingbeneficial or desired results including clinical results. For purposesof this invention, beneficial or desired clinical results include, butare not limited to, one or more of the following: alleviating one ormore symptoms resulting from the disease, diminishing the extent of thedisease, stabilizing the disease (e.g., preventing or delaying theworsening of the disease), suppressing or delaying the spread (e.g.,metastasis) of the disease, preventing or delaying the recurrence of thedisease, delaying or slowing the progression of the disease,ameliorating the disease state, providing a remission (partial or total)of the disease, decreasing the dose of one or more other medicationsrequired to treat the disease, delaying the progression of the disease,increasing or improving the quality of life, increasing weight gain,and/or prolonging survival. Also encompassed by “treatment” is areduction of pathological consequence of cancer. The methods of theinvention contemplate any one or more of these aspects of treatment.

The term “effective amount” used herein refers to an amount of acompound or composition sufficient to treat a specified disorder,condition or disease such as to ameliorate, palliate, lessen, and/ordelay one or more of its symptoms. In reference to cancers, an effectiveamount comprises an amount sufficient to cause a tumor to shrink and/orto decrease the growth rate of the tumor (such as to suppress tumorgrowth) and/or to suppress, or delay other unwanted cell proliferationand/or to treat or suppress tumor metastasis and/or to reduce (such aseradiate) preexisting tumor metastasis and/or to reduce incidence orburden of preexisting tumor metastasis and/or to suppress or delay tumormetastasis and/or to inhibit tumor cells and/or to induce an immuneresponse against a tumor cell. An effective amount can be administeredin one or more administrations, for example, the effective amount of thedrug or composition may: (i) reduce the number of cancer cells; (ii)reduce tumor size; (iii) inhibit, retard, slow to some extent andpreferably stop cancer cell infiltration into peripheral organs; (iv)inhibit (i.e., slow to some extent and preferably stop) tumormetastasis; (v) inhibit tumor growth; (vi) suppress or delay occurrenceand/or recurrence of tumor; and/or (vii) relieve to some extent one ormore of the symptoms associated with the cancer.

The term “nucleoside analog” is a nucleoside structurally similar to thenaturally occurring residues in RNA and DNA, used in medicine and inmolecular biology, and which may be incorporated, e.g. chemically, intoan oligonucleotide or nucleic acid by formation of a phosphodiester bondor equivalent with one or two residues of the residue chain depending onwhether the nucleoside analog is in a terminal or intra-chain position,respectively. Nucleic acids are chains of nucleotides, which arecomposed of three parts: a phosphate backbone, a pucker-shaped pentosesugar, either ribose or deoxyribose, and one of five nucleobases. Anucleoside analogue differs from a nucleoside by having any one or moreof its hydroxyl, base or sugar groups altered, and the alteration doesnot prevent the nucleoside analogue from being incorporated into anoligonucleotide such as an aptamer, internalizing nucleic acid ortumor-homing nucleic acid.

Methods of the Present Invention

The present invention in one aspect provides a method of inhibitingtumor cell growth at a second tumor site distinct from a first tumorsite in the bladder of an individual, comprising locally delivering tothe bladder an effective amount of a chemotherapeutic agent (such as anucleoside analog, for example gemcitabine), wherein thechemotherapeutic agent is delivered continuously, for example for atleast about 24 hours. In some embodiments, the chemotherapeutic agent isimmunogenic. In some embodiments, the chemotherapeutic agent induces anecrosis event. In some embodiment, the chemotherapeutic agent isselected from the group consisting of nucleoside analog (e.g.gemcitabine and capecitabine), taxane (e.g. docetaxel and cabazitaxel),platinum-based agent (e.g. oxaliplatin), anthracycline analogue (e.g.doxorubicin, idarubicin), and mitoxantrone. In some embodiments, thetumor cells at the second tumor site result from metastasis of a primarytumor at the first tumor site. In some embodiments, the tumor cells atthe second tumor site are from a secondary tumor. In some embodiments,the tumor cells at the second tumor site are circulating tumor cells. Insome embodiments, the tumor cells at the first tumor site result frommetastasis of a primary tumor at the second tumor site.

In some embodiments, the chemotherapeutic agent is a nucleoside analogsuch as gemcitabine or capecitabine. In some embodiments, thechemotherapeutic agent is a taxane such as paclitaxel, cabazitaxel, ordocetaxel. In some embodiments, the chemotherapeutic agent is aplatinum-based agent such as oxaliplatin. In some embodiments, thechemotherapeutic agent is an anthracycline analogue such as doxorubicin.In some embodiments, the tumor cells at the second tumor site resultfrom metastasis of a primary tumor at the first tumor site. For example,in some embodiments, there is provided a method of treating tumormetastasis at a site distinct from the bladder in an individual having aurothelial carcinoma of the lower tract, comprising locally deliveringto the bladder an effective amount of a chemotherapeutic agent (such asa nucleoside analog, for example gemcitabine), wherein thechemotherapeutic agent is delivered continuously to the bladder, forexample for at least about 24 hours. In some embodiments, there isprovided a method of suppressing tumor metastasis at a site distinctfrom the bladder in an individual having a urothelial carcinoma of thelower tract, comprising locally delivering to the bladder an effectiveamount of a chemotherapeutic agent (such as a nucleoside analog, forexample gemcitabine), wherein the chemotherapeutic agent is deliveredcontinuously to the bladder, for example for at least about 24 hours. Insome embodiments, the chemotherapeutic agent is delivered continuouslyto the bladder for about 3 weeks. In some embodiments, thechemotherapeutic agent is delivered continuously to the bladder forabout 12 weeks. In some embodiments, the chemotherapeutic agent isimmunogenic. In some embodiments, the chemotherapeutic agent induces anecrosis event. In some embodiments, the tumor at the second tumor siteis at one or more (such as two, three, four, five, six, or seven) of:liver, lung, bone, brain, lymph node, pelvic node, peritoneum, skin,prostate, breast, colon, rectum, cervix. In some embodiments, the tumormetastatic site is at two, three, four, five, six, or more sites. Insome embodiments, at least about 10% (including for example at leastabout any of 20%, 30%, 40%, 60%, 70%, 80%, 90%, or 100%) metastasis isinhibited. In some embodiments, the tumor metastasis is at two differentsites. In some embodiments, the tumor metastasis is at two sites in thesame organ. In some embodiments, the tumor metastasis is at two sites indifferent organs. In some embodiments, the tumor metastasis is at morethan two sites. In some embodiments, the tumor metastasis is at morethan two different sites. In some embodiments, for example when themetastasis is to the lung, the total area of involvement is decreased.In some embodiments, the patient has a cancer stage of M0 followingtreatment. In some embodiments, the patient has a cancer stage of N1 orN0 following treatment.

In some embodiments, the individual has a tumor in the bladder. In someembodiments, the individual has a urothelial carcinoma of the lowertract. In some embodiments the individual has a squamous carcinoma,adenocarcinoma, sarcomatoid, or small cell carcinoma in the bladder. Insome embodiments, the individual has a histologically variant subtype ofa urothelial carcinoma of the lower tract, such as pappilary,micropapillary, or carcinoma in situ. In some embodiments, theindividual has an infiltrating urothelial carcinoma of lower tract suchas a transitional cell carcinoma (e.g. micropappliary or spindle cell),a lymphopithelial carcinoma, a schmincke tumor, or a giant cellcarcinoma. In some embodiments the individual has a non-invasiveurothelial neoplasia such as a transitional cell carcinoma in situ, anon-invasive pappilary transitional cell carcinoma, a papillarytransitional cell neoplasm of low malignant potential, or a urothelialpapilloma. In some embodiments, the individual has a squamous neoplasm,such as a squamous cell carcinoma, a verrucous carcinoma, or a squamouscell papilloma. In some embodiments, the individual has a glandularneoplasm, such as an adenocarcinoma or a villous adenoma.

In some embodiments, there is provided a method of treating tumormetastasis at a site distinct from the bladder in an individual havingbladder cancer, comprising locally delivering to the bladder aneffective amount of a chemotherapeutic agent (such as a nucleosideanalog, for example gemcitabine), wherein the chemotherapeutic agent isdelivered continuously to the bladder, for example for at least about 24hours. In some embodiments, the chemotherapeutic agent is deliveredcontinuously to the bladder for about 3 weeks. In some embodiments, thechemotherapeutic agent is delivered continuously to the bladder forabout 12 weeks. In some embodiments, there is provided a method ofsuppressing tumor metastasis at a site distinct from the bladder in anindividual having bladder cancer, comprising locally delivering to thebladder an effective amount of a chemotherapeutic agent (such as anucleoside analog, for example gemcitabine), wherein thechemotherapeutic agent is delivered continuously to the bladder, forexample for at least about 24 hours. In some embodiments, at least about10% (including for example at least about any of 20%, 30%, 40%, 60%,70%, 80%, 90%, or 100%) metastasis is inhibited. In some embodiments,the chemotherapeutic agent is immunogenic. In some embodiments, thechemotherapeutic agent induces a necrosis event. In some embodiments,the tumor metastatic site is at one or more (such as two, three, four,five, six, or seven) of: liver, lung, bone, brain, lymph node, pelvicnode, peritoneum, skin, prostate, breast, colon, rectum, cervix. In someembodiments, the tumor metastatic site is at two, three, four, five,six, or more sites. In some embodiments, the individual hasmuscle-invasive bladder cancer. In some embodiments, the individual hascarcinoma in situ (CIS). In some embodiments, the individual is unfitfor or refuses cystectomy. In some embodiments, the individual has notundergone transurethral resection of bladder tumors (TURBT). In someembodiments, the individual has undergone transurethral resection ofbladder tumors (TURBT). In some embodiments, the individual hasundergone transurethral resection of bladder tumors (TURBT), and hasresidual tumor cells at the site of resection, for example sufficientresidual tumor cells to trigger an immune response. In some embodiments,the individual has Ta, Tis, T1, T2, T2a, T2b, T3, T3a, T4, T4a, or T4bcancer following TURBT. In some embodiments, the chemotherapeutic agentis delivered both prior to TURBT and after TURBT. In some embodiments,the chemotherapeutic agent concentration in the plasma of the individualduring the period of continuous delivery is less than about 1 μg/mL,such as less than about any of 0.5, 0.4, 0.3, 0.2, 0.1, 0.05, 0.04,0.03, 0.02, or 0.01 μg/mL during the delivery period. In someembodiments, the concentration of the chemotherapeutic agent or activemetabolite thereof in the plasma of the individual is at asubtherapeutic level during the delivery period.

In some embodiments, there is provided a method of reducing (such aseradicating) preexisting non-bladder resident tumor metastasis at a sitedistinct from the bladder in an individual having a urothelial carcinomaof lower tract, comprising locally delivering to the bladder aneffective amount of a chemotherapeutic agent (such as a nucleosideanalog, for example gemcitabine), wherein the chemotherapeutic agent isdelivered continuously to the bladder, for example for at least about 24hours. In some embodiments, the chemotherapeutic agent is deliveredcontinuously to the bladder for about 3 weeks. In some embodiments, thechemotherapeutic agent is delivered continuously to the bladder forabout 12 weeks. In some embodiments, there is provided a method ofreducing (such as eradicating) preexisting non-bladder resident tumormetastasis at a site distinct from the bladder in an individual havingbladder cancer, comprising locally delivering to the bladder aneffective amount of a chemotherapeutic agent (such as a nucleosideanalog, for example gemcitabine), wherein the chemotherapeutic agent isdelivered continuously to the bladder, for example for at least about 24hours. In some embodiments, the chemotherapeutic agent is deliveredcontinuously to the bladder for about 3 weeks. In some embodiments, thechemotherapeutic agent is delivered continuously to the bladder forabout 12 weeks. In some embodiments, the chemotherapeutic agent isimmunogenic. In some embodiments, the chemotherapeutic agent induces anecrosis event. In some embodiments, at least about 10% (including forexample at least about any of 20%, 30%, 40%, 60%, 70%, 80%, 90%, or100%) metastasis is reduced. In some embodiments, the tumor metastaticsite is at one or more (such as two, three, four, five, six, or seven)of: liver, lung, bone, brain, lymph node, pelvic node, peritoneum, skin,prostate, breast, colon, rectum, and cervix. In some embodiments, thetumor metastatic site is at two, three, four, five, six, or more sites.In some embodiments, the individual has muscle-invasive bladder cancer.In some embodiments, the individual has carcinoma in situ (CIS). In someembodiments, the individual has not undergone transurethral resection ofbladder tumors (TURBT). In some embodiments, the individual hasundergone transurethral resection of bladder tumors (TURBT). In someembodiments, the individual has undergone transurethral resection ofbladder tumors (TURBT), and has residual tumor cells at the site ofresection, for example sufficient residual tumor cells to trigger animmune response. In some embodiments, the individual has Ta, Tis, T1,T2, T2a, T2b, T3, T3a, T4, T4a, or T4b cancer following TURBT. In someembodiments, the chemotherapeutic agent is delivered both prior to TURBTand after TURBT. In some embodiments, the chemotherapeutic agentconcentration in the plasma of the individual during the period ofcontinuous delivery is less than about 1 μg/mL, such as less than aboutany of 0.5, 0.4, 0.3, 0.2, 0.1, 0.05, 0.04, 0.03, 0.02, or 0.01 μg/mLduring the delivery period. In some embodiments, the concentration ofthe chemotherapeutic agent or active metabolite thereof in the plasma ofthe individual is at a subtherapeutic level during the delivery period.

In some embodiments, there is provided a method of reducing incidence orburden of preexisting non-bladder resident tumor at a site distinct fromthe bladder in an individual having a urothelial carcinoma of lowertract, comprising locally delivering to the bladder an effective amountof a chemotherapeutic agent (such as a nucleoside analog, for examplegemcitabine), wherein the chemotherapeutic agent is deliveredcontinuously to the bladder, for example for at least about 24 hours. Insome embodiments, there is provided a method of reducing incidence orburden of preexisting non-bladder resident tumor at a site distinct fromthe bladder in an individual having bladder cancer, comprising locallydelivering to the bladder an effective amount of a chemotherapeuticagent (such as a nucleoside analog, for example gemcitabine), whereinthe chemotherapeutic agent is delivered continuously to the bladder, forexample for at least about 24 hours. In some embodiments, the tumormetastatic site is at one or more (such as two, three, four, five, six,or seven) of: liver, lung, bone, brain, lymph node, pelvic node,peritoneum, skin, prostate, breast, colon, rectum, cervix. In someembodiments, the tumor metastatic site is at two, three, four, five,six, or more sites. In some embodiments, the chemotherapeutic agent isimmunogenic. In some embodiments, the chemotherapeutic agent induces anecrosis event. In some embodiments, the individual has muscle-invasivebladder cancer. In some embodiments, the individual has carcinoma insitu (CIS). In some embodiments, the individual is unfit for or refusescystectomy. In some embodiments, the individual has not undergonetransurethral resection of bladder tumors (TURBT). In some embodiments,the individual has undergone transurethral resection of bladder tumors(TURBT). In some embodiments, the individual has undergone transurethralresection of bladder tumors (TURBT), and has residual tumor cells at thesite of resection, for example sufficient residual tumor cells totrigger an immune response. In some embodiments, the individual has Ta,Tis, T1, T2, T2a, T2b, T3, T3a, T4, T4a, or T4b cancer following TURBT.In some embodiments, the chemotherapeutic agent is delivered both priorto TURBT and after TURBT. In some embodiments, the chemotherapeuticagent concentration in the plasma of the individual during the period ofcontinuous delivery is less than about 1 μg/mL, such as less than aboutany of 0.5, 0.4, 0.3, 0.2, 0.1, 0.05, 0.04, 0.03, 0.02, or 0.01 μg/mLduring the delivery period. In some embodiments, the concentration ofthe chemotherapeutic agent or active metabolite thereof in the plasma ofthe individual is at a subtherapeutic level during the delivery period.

In some embodiments, there is provided a method of inducing immuneresponse against a tumor cell at a second tumor site distinct from afirst tumor site in the bladder of an individual, comprising locallydelivering to the bladder an effective amount of a chemotherapeuticagent (such as a nucleoside analog, for example gemcitabine), whereinthe chemotherapeutic agent is delivered continuously, for example for atleast about 24 hours. In some embodiments, the chemotherapeutic agent isdelivered continuously to the bladder for about 3 weeks. In someembodiments, the chemotherapeutic agent is delivered continuously to thebladder for about 12 weeks. In some embodiments, there is provided amethod of improving tumor microenvironment for cancer therapy at asecond tumor site distinct from a first tumor site in the bladder of anindividual, comprising locally delivering to the bladder an effectiveamount of a chemotherapeutic agent (such as a nucleoside analog, forexample gemcitabine), wherein the chemotherapeutic agent is deliveredcontinuously, for example for at least about 24 hours. In someembodiments, the tumor cells at the second tumor site result frommetastasis of a primary tumor at the first tumor site. In someembodiments, the tumor at the second tumor site is at one or more (suchas two, three, four, five, six, or seven) of: liver, lung, bone, brain,lymph node, pelvic node, peritoneum, skin, prostate, breast, colon,rectum, cervix. In some embodiments, the tumor cells at the second tumorsite are from a secondary tumor. In some embodiments, the tumor cells atthe second tumor site are circulating tumor cells. In some embodiments,the tumor cells at the first tumor site result from metastasis of aprimary tumor at the second tumor site. In some embodiments, thechemotherapeutic agent is selected from the group consisting of anucleoside analog (e.g. gemcitabine and capecitabine), a taxane (e.g.docetaxel and cabazitaxel), a platinum-based agent (e.g. oxaliplatin,cisplatin or carboplatin), an anthracycline analogue (e.g. doxorubicin,idarubicin), and mitoxantrone. In some embodiments, the chemotherapeuticagent is immunogenic. In some embodiments, the chemotherapeutic agentinduces a necrosis event. In some embodiments, the level of apro-inflammatory cytokine (such as TNF-α or IFN-γ) is increased. In someembodiments, the level of an anti-inflammatory cytokine (such as TGF-β)is decreased.

In some embodiments, the level or the activity of an immune cellpopulation is altered at the second site. In some embodiments, the levelor the activity of regulatory T cells is decreased. In some embodiments,the level or the activity of effector T cells is increased. In someembodiments, the level or activity of helper T cells is increased. Insome embodiments, the level or the activity of memory cells isincreased. In some embodiments, the level or the activity ofplasmablasts is increased. One of skill in the art will be aware ofvarious methods to measure the presence of regulatory T cells or otherimmune cell population in a sample, such as immunohistochemicallystaining for relevant markers or performing flow cytometry or FACSanalysis. For example, the level or percentage of regulatory T cells mayalso be decreased relatively compared to conventional T cells that areCD4+CD25−.

In some embodiments, the immune response is induced by an acuteinflammation event. In some embodiments, the acute inflammation event istriggered by the continuous delivery of a chemotherapeutic agent. Insome embodiments, the chemotherapeutic agent is immunogenic. In someembodiments, the chemotherapeutic agent induces a necrosis event. Insome embodiments, the immune response is an innate immune response. Insome embodiments, the innate immune response is characterized by anincreased population of activation of antigen presenting cells such asdendritic cells and/or macrophages in the bladder or in peripheral bloodor at the second tumor site. In some embodiments, the innate immuneresponse is characterized by the increased level of tumor antigenpresentation by antigen presentation cells (APCs, such as dendriticcells and/or macrophages). In some embodiments, the innate immuneresponse is characterized by the increased level of tumor antigenpresentation by antigen presentation cells (APCs, such as dendriticcells and/or macrophages) at the second site. In some embodiments, theincreased level of tumor antigen presentation by APCs is triggered bythe continuous delivery of the chemotherapeutic agent (such asgemcitabine).

In some embodiments, the immune response is an adaptive immune response.In some embodiments, the adaptive immune response is characterized by anincreased level of immune cell population. In some embodiments, theadaptive immune response is characterized by an increased level ofmemory B cells in peripheral blood or tissues. In some embodiments, theadaptive immune response is characterized by an increased level ofmemory T cells in peripheral blood or tissues. In some embodiments, theadaptive immune response is characterized by an increased level ofmemory B cells at the second tumor site. In some embodiments, theadaptive immune response is characterized by an increased level ofmemory T cells at the second tumor site. In some embodiments, theadaptive immune response is characterized by an increased activationlevel of memory B cells in peripheral blood or tissues. In someembodiments, the adaptive immune response is characterized by anincreased activation level of memory T cells in peripheral blood ortissues. In some embodiments, the adaptive immune response ischaracterized by an increased activation level of memory B cells at thesecond tumor site. In some embodiments, the adaptive immune response ischaracterized by an increased activation level of memory T cells at thesecond tumor site. In some embodiments, the continuous delivery of thechemotherapeutic agents induces both innate and adaptive immuneresponse.

In some embodiments, the tumor cells at the second tumor site are from asecondary tumor. In some embodiments, there is provided a method ofinhibiting the growth of a secondary tumor at a second tumor sitedistinct from a first tumor site in the bladder of an individual,comprising locally delivering to the bladder an effective amount of achemotherapeutic agent (such as a nucleoside analog, for examplegemcitabine), wherein the chemotherapeutic agent is deliveredcontinuously, for example for at least about 24 hours. In someembodiments, the chemotherapeutic agent is delivered continuously to thebladder for about 3 weeks. In some embodiments, the chemotherapeuticagent is delivered continuously to the bladder for about 12 weeks. Insome embodiments, the chemotherapeutic agent is immunogenic. In someembodiments, the chemotherapeutic agent induces a necrosis event. Insome embodiments, the individual has bladder cancer. In someembodiments, the individual has muscle-invasive bladder cancer. In someembodiments, the individual has carcinoma in situ (CIS). In someembodiments, the individual is unfit for or refuses cystectomy. In someembodiments, the individual has not undergone transurethral resection ofbladder tumors (TURBT). In some embodiments, the individual hasundergone transurethral resection of bladder tumors (TURBT). In someembodiments, the individual has undergone transurethral resection ofbladder tumors (TURBT), and has residual tumor cells at the site ofresection, for example sufficient residual tumor cells to trigger animmune response. In some embodiments, the individual has Ta, Tis, T1,T2, T2a, T2b, T3, T3a, T4, T4a, or T4b cancer following TURBT. In someembodiments, the chemotherapeutic agent is delivered both prior to TURBTand after TURBT. In some embodiments, the chemotherapeutic agentconcentration in the plasma of the individual during the period ofcontinuous delivery is less than about 1 μg/mL, such as less than aboutany of 0.5, 0.4, 0.3, 0.2, 0.1, 0.05, 0.04, 0.03, 0.02, or 0.01 μg/mLduring the delivery period. In some embodiments, the concentration ofthe chemotherapeutic agent or active metabolite thereof in the plasma ofthe individual is at a subtherapeutic level during the delivery period.

In some embodiments, tumor volume at the second site is reduced at leastabout 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%,70%, 75% 80%, 85%, 90%, 95%, or 99% upon treatment with achemotherapeutic agent (such as gemcitabine). In some embodiments, tumorcells at a second site distinct from a first tumor site are inhibited bydelaying the appearance or development of tumor cells at a second site.In some embodiments, the growth of tumor cells at a second site isreduced for at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%,50%, 55%, 60%, 65%, 70%, 75% 80%, 85%, 90%, 95%, or 99% upon treatmentwith a chemotherapeutic agent (such as gemcitabine). In someembodiments, tumor cells at a second site distinct from a first tumorsite are delayed in their appearance or development for at least about7, 14, 21, 28, or 35 days upon the continuous local treatment with achemotherapeutic agent (such as gemcitabine) at the first tumor site, ascompared to the tumor cells in comparable conditions without thecontinuous, local delivery of the chemotherapeutic agent (such asgemcitabine) in the first site in the bladder of an individual. In someembodiments, tumor cells at a second site distinct from a first tumorsite are delayed in their appearance or development for at least about1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months upon the continuous,local treatment with a chemotherapeutic agent (such as gemcitabine) atthe first site, as compared to the tumor cells in comparable conditionswithout the continuous, local delivery of the chemotherapeutic agent inthe first site in the bladder of an individual.

In some embodiments, the tumor cells at the second tumor site arecirculating tumor cells. In some embodiments, there is provided a methodof inhibiting the release of circulating tumor cells at a second tumorsite distinct from a first tumor site in the bladder of an individual,comprising locally delivering to the bladder an effective amount of achemotherapeutic agent (such as a nucleoside analog, for examplegemcitabine), wherein the chemotherapeutic agent is deliveredcontinuously, for example for at least about 24 hours. In someembodiments, the chemotherapeutic agent is delivered continuously to thebladder for about 3 weeks. In some embodiments, the chemotherapeuticagent is delivered continuously to the bladder for about 12 weeks. Insome embodiments, the chemotherapeutic agent is immunogenic. In someembodiments, the chemotherapeutic agent induces a necrosis event. Insome embodiments, the individual has bladder cancer. In someembodiments, the individual has muscle-invasive bladder cancer. In someembodiments, the individual has carcinoma in situ (CIS). In someembodiments, the individual is unfit for or refuses cystectomy. In someembodiments, the individual has not undergone transurethral resection ofbladder tumors (TURBT). In some embodiments, the individual hasundergone transurethral resection of bladder tumors (TURBT). In someembodiments, the individual has undergone transurethral resection ofbladder tumors (TURBT), and has residual tumor cells at the site ofresection, for example sufficient residual tumor cells to trigger animmune response. In some embodiments, the individual has Ta, Tis, T1,T2, T2a, T2b, T3, T3a, T4, T4a, or T4b cancer following TURBT. In someembodiments, the chemotherapeutic agent is delivered both prior to TURBTand after TURBT. In some embodiments, the chemotherapeutic agentconcentration in the plasma of the individual during the period ofcontinuous delivery is less than about 1 μg/mL, such as less than aboutany of 0.5, 0.4, 0.3, 0.2, 0.1, 0.05, 0.04, 0.03, 0.02, or 0.01 μg/mLduring the delivery period. In some embodiments, the concentration ofthe chemotherapeutic agent or active metabolite thereof in theindividual is at a subtherapeutic level during the delivery period.

In some embodiments, circulating tumor cells are reduced upon thetreatment with the chemotherapeutic agent. In some embodiments,circulating tumor cells are tumor cells in the peripheral blood of anindividual. In some embodiments, circulating tumor cells are tumor cellsin the cerebrospinal fluid of an individual. Circulating tumor cells canbe tumor cells that have not implanted in an organ. Circulating tumorcells can be readily tested with the CELLSEARCH CTC Test or otherroutine procedures. In some embodiments, the circulating tumor cells arereduced by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%,50%, 55%, 60%, 65%, 70%, 75% 80%, 85%, 90%, 95%, or 99%. In someembodiments, the appearance or development of circulating tumor cells isdelayed. In some embodiments, the growth of circulating tumor cells isreduced by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%,50%, 55%, 60%, 65%, 70%, 75% 80%, 85%, 90%, 95%, or 99%. In someembodiments, the appearance or development of circulating tumor cells isdelayed for at least about 7, 14, 21, 28 or 35 days. In someembodiments, the appearance or development of circulating tumor cells isdelayed for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12months. In some embodiments, the appearance or development ofcirculating tumor cells is delayed for at least 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11 or 12 years.

In some embodiments, the tumor cells at the first tumor site result frommetastasis of a primary tumor at the second tumor site. In someembodiments, the tumor cells at the first tumor site result from asecondary tumor of an individual having a primary tumor at the secondtumor site. For example, in some embodiments, the individual has aprimary cancer at a second tumor site that metastasized to the bladder.In some embodiments, the individual has a primary cancer at a sitedistinct from the bladder and a secondary cancer in the bladder. In someembodiments, the primary cancer is selected from the group consisting ofprostate cancer, breast cancer, colorectal cancer, and cervical cancer.

Thus, for example, in some embodiments, there is provided a method oftreating a prostate cancer at a second tumor site distinct from thebladder of an individual, wherein the cancer has metastasized to thebladder, comprising locally delivering to the bladder an effectiveamount of a chemotherapeutic agent (such as a nucleoside analog, forexample gemcitabine), wherein the chemotherapeutic agent is deliveredcontinuously, for example for at least about 24 hours. In someembodiments, the chemotherapeutic agent is immunogenic. In someembodiments, the chemotherapeutic agent induces a necrosis event. Insome embodiments, when the individual has prostate cancer at a secondtumor site that has metastasized to the bladder, the tumor volume at thesecond site in the prostate is reduced by at least about 5%, 10%, 15%,25%, 30%, 35%, 40%, 45%, 55%, 60%, 65%, 70%, 75% 80%, 85%, 90%, 95%, or99% upon treatment with a chemotherapeutic agent (such as gemcitabine).In some embodiments, the growth of tumor cells at the second site in theprostate is reduced for at least about 5%, 10%, 15%, 25%, 30%, 35%, 40%,45%, 55%, 60%, 65%, 70%, 75% 80%, 85%, 90%, 95%, or 99% upon treatmentwith a chemotherapeutic agent (such as gemcitabine). In someembodiments, the chemotherapeutic agent concentration in the plasma ofthe individual during the period of continuous delivery is less thanabout 1 μg/mL, such as less than about any of 0.5, 0.4, 0.3, 0.2, 0.1,0.05, 0.04, 0.03, 0.02, or 0.01 μg/mL during the delivery period. Insome embodiments, the concentration of the chemotherapeutic agent oractive metabolite thereof in the plasma of the individual is at asubtherapeutic level during the delivery period.

In some embodiments, there is provided a method of treating breastcancer at a second tumor site distinct from the bladder of anindividual, wherein the cancer has metastasized to the bladder,comprising locally delivering to the bladder an effective amount of achemotherapeutic agent (such as a nucleoside analog, for examplegemcitabine), wherein the chemotherapeutic agent is deliveredcontinuously, for example for at least about 24 hours. In someembodiments, the chemotherapeutic agent is immunogenic. In someembodiments, the chemotherapeutic agent induces a necrosis event. Insome embodiments, the metastasis to the bladder is an adenocarcinoma. Insome embodiments, when the individual has breast cancer at a secondtumor site that has metastasized to the bladder, the tumor volume at thesecond site in the breast is reduced by at least about 5%, 10%, 15%,25%, 30%, 35%, 40%, 45%, 55%, 60%, 65%, 70%, 75% 80%, 85%, 90%, 95%, or99% upon treatment with a chemotherapeutic agent (such as gemcitabine).In some embodiments, the growth of tumor cells at the second site in thebreast is reduced for at least about 5%, 10%, 15%, 25%, 30%, 35%, 40%,45%, 55%, 60%, 65%, 70%, 75% 80%, 85%, 90%, 95%, or 99% upon treatmentwith a chemotherapeutic agent (such as gemcitabine). In someembodiments, the chemotherapeutic agent concentration in the plasma ofthe individual during the period of continuous delivery is less thanabout 1 μg/mL, such as less than about any of 0.5, 0.4, 0.3, 0.2, 0.1,0.05, 0.04, 0.03, 0.02, or 0.01 μg/mL during the delivery period. Insome embodiments, the concentration of the chemotherapeutic agent oractive metabolite thereof in the plasma of the individual is at asubtherapeutic level during the delivery period.

In some embodiments, there is provided a method of treating colorectalcancer at a second tumor site distinct from the bladder of anindividual, wherein the cancer has metastasized to the bladder,comprising locally delivering to the bladder an effective amount of achemotherapeutic agent (such as a nucleoside analog, for examplegemcitabine), wherein the chemotherapeutic agent is deliveredcontinuously, for example for at least about 24 hours. In someembodiments, the chemotherapeutic agent is immunogenic. In someembodiments, the chemotherapeutic agent induces a necrosis event. Insome embodiments, when the individual has colorectal cancer at a secondtumor site that has metastasized to the bladder, the tumor volume at thesecond site in the colon or rectum is reduced by at least about 5%, 10%,15%, 25%, 30%, 35%, 40%, 45%, 55%, 60%, 65%, 70%, 75% 80%, 85%, 90%,95%, or 99% upon treatment with a chemotherapeutic agent (such asgemcitabine). In some embodiments, the growth of tumor cells at thesecond site in the colon or rectum is reduced for at least about 5%,10%, 15%, 25%, 30%, 35%, 40%, 45%, 55%, 60%, 65%, 70%, 75% 80%, 85%,90%, 95%, or 99% upon treatment with a chemotherapeutic agent (such asgemcitabine). In some embodiments, the chemotherapeutic agentconcentration in the plasma of the individual during the period ofcontinuous delivery is less than about 1 μg/mL, such as less than aboutany of 0.5, 0.4, 0.3, 0.2, 0.1, 0.05, 0.04, 0.03, 0.02, or 0.01 μg/mLduring the delivery period. In some embodiments, the concentration ofthe chemotherapeutic agent or active metabolite thereof in the plasma ofthe individual is at a subtherapeutic level during the delivery period.

In some embodiments, there is provided a method of treating cervicalcancer at a second tumor site distinct from the bladder of anindividual, wherein the cancer has metastasized to the bladder,comprising locally delivering to the bladder an effective amount of achemotherapeutic agent (such as a nucleoside analog, for examplegemcitabine), wherein the chemotherapeutic agent is deliveredcontinuously, for example for at least about 24 hours. In someembodiments, the chemotherapeutic agent is immunogenic. In someembodiments, the chemotherapeutic agent induces a necrosis event. Insome embodiments, when the individual has cervical cancer at a secondtumor site that has metastasized to the bladder, the tumor volume at thesecond site in the cervix is reduced by at least about 5%, 10%, 15%,25%, 30%, 35%, 40%, 45%, 55%, 60%, 65%, 70%, 75% 80%, 85%, 90%, 95%, or99% upon treatment with a chemotherapeutic agent (such as gemcitabine).In some embodiments, the growth of tumor cells at the second site in thecervix is reduced for at least about 5%, 10%, 15%, 25%, 30%, 35%, 40%,45%, 55%, 60%, 65%, 70%, 75% 80%, 85%, 90%, 95%, or 99% upon treatmentwith a chemotherapeutic agent (such as gemcitabine). In someembodiments, the chemotherapeutic agent concentration in the plasma ofthe individual during the period of continuous delivery is less thanabout 1 μg/mL, such as less than about any of 0.5, 0.4, 0.3, 0.2, 0.1,0.05, 0.04, 0.03, 0.02, or 0.01 μg/mL during the delivery period. Insome embodiments, the concentration of the chemotherapeutic agent oractive metabolite thereof in the plasma of the individual is at asubtherapeutic level during the delivery period.

The chemotherapeutic agent in the methods described herein is deliveredcontinuously to the bladder. In some embodiments, the chemotherapeuticagent is continuously delivered for at least about 24 hours, includingfor example at least about any of 2, 3, 4, 5, 6, or 7 days. In someembodiments the chemotherapeutic agent is continuously delivered to thebladder for 7 days or less. In some embodiments, the chemotherapeuticagent is continuously delivered to the bladder for a period of about 7days to about three weeks. In some embodiments, the chemotherapeuticagent (such as gemcitabine) is delivered continuously to the bladder forat least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 days. Insome embodiments, the chemotherapeutic agent (such as gemcitabine) isdelivered continuously to the bladder for at least 24-48 hours. In someembodiments, the chemotherapeutic agent (such as gemcitabine) isdelivered continuously to the bladder for at least about 2-4, 4-8, 5-10,7-14 or 18-24 days. In some embodiments, the concentration in the plasmaof the individual during the period of continuous delivery is less thanabout 1 μg/mL, such as less than about any of 0.5, 0.4, 0.3, 0.2, 0.1,0.05, 0.04, 0.03, 0.02, or 0.01 μg/mL during the delivery period. Insome embodiments, the ratio of chemotherapeutic agent in the urine tochemotherapeutic agent in the plasma of the individual during the periodof continuous delivery is greater than about 500:1 during the deliveryperiod. Continuous delivery discussed herein also encompasses deliveryof the chemotherapeutic agent in regular or irregular pulses, forexample, to maintain a sustained level of the chemotherapeutic agent inthe bladder. In some embodiments, the urine level of thechemotherapeutic agent in the individual is at least about 0.1 μg/mLthroughout continuous delivery period. In some embodiments, theconcentration of the chemotherapeutic agent or active metabolite thereofin the plasma of the individual is at a subtherapeutic level during thedelivery period.

In some embodiments, the method comprises at least two separate cyclesof continuous delivery. For example, the chemotherapeutic agent iscontinuously delivered to the bladder for a first period of time, whichis followed by a rest period where no chemotherapeutic agent isdelivered. Following the rest period, the chemotherapeutic agent iscontinuously delivered to the bladder for a second period of time. Insome embodiments, the first and the second periods are each about 7 daysto about three weeks. In some embodiments, the rest period is about 7days to about two weeks. In some embodiments, the rest period is about3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks. In some embodiments, the restperiod is about 1-12 weeks. In some embodiments, the first and thesecond periods are each about 7 days to about two weeks. The methodsdescribed herein can be particularly effective when comprising at leasttwo separate cycles of continuous delivery. Without being bound by thetheory, it is believed that the first delivery period may causepresentation of neoantigen which triggers an innate and adaptive immuneresponse. In the second dose, the neoantigen is released again whichcauses a stronger immune response. In some embodiments, the methodcomprises an induction period, a rest period, and a maintenance period,wherein the urine concentration of the chemotherapeutic agent during theinduction and maintenance periods is at least about 0.1 μg/mL, andwherein the urine concentration of the chemotherapeutic agent during therest period is less than about 0.01 μg/mL (for example below detectionlimit). In some embodiments, the chemotherapeutic agent concentration inthe plasma of the individual during the period of continuous delivery isless than about 1 μg/mL, such as less than about any of 0.5, 0.4, 0.3,0.2, 0.1, 0.05, 0.04, 0.03, 0.02, or 0.01 μg/mL during the deliveryperiod. In some embodiments, the concentration of the chemotherapeuticagent or active metabolite thereof in the plasma of the individual is ata subtherapeutic level during the delivery period.

In some embodiments, the first phase is about 5-9 or 6-8 days. In someembodiments, the first phase is at least 24 or 48 hours. In someembodiments, the first phase is less than 48 hours. In some embodiments,the first phase is about 7 days. In some embodiments, the first phase isabout 14 days. In some embodiments, the first phase is about 24 hours.In some embodiments, the second phase is about 5-9 or 6-8 days. In someembodiments, the second phase is at least 24 or 48 hours. In someembodiments, the second phase is less than 1.5, 3, 6, 12, 24 or 48hours. In some embodiments, the second phase is about 7 days. In someembodiments, the second phase is about 14 days. In some embodiments, thesecond phase is about 24 hours. In some embodiments, the first phase isthe same as the second phase. In some embodiments, the first phase isdifferent from the second phase. In some embodiments, the rest phase isat least 24 or 48 hours. In some embodiments, the rest phase is about 7or 14 days. In some embodiments, the rest period is less than 6, 12, 24or 48 hours. In some embodiments, the first dose is the same as thesecond dose. In some embodiments, the first dose is different from thesecond dose. In some embodiments, each of the first dose and/or thesecond dose is about 1 mg/day to about 300 mg/day (such as 225 mg/day).

Other dosing regimens suitable for the methods described herein arefurther described in the specific section below.

Continuous delivery of chemotherapeutic agent can be carried out byvarious methods known in the art, including, for example, via bladderperfusion of drug solution, or via a coating substance intravesicallyapplied to the bladder wall (for example a gel), or via an intravesicaldelivery device as further described below in more detail. In someembodiments, the chemotherapeutic agent is delivered by perfusion. Insome embodiments, the chemotherapeutic agent is delivered by amicrochip, as described for example in U.S. Publication 2008/0221557.

The delivery of the chemotherapeutic agent described herein in someembodiments can be carried out using an intravesical delivery device.Various intravesical delivery devices are described herein. In someembodiments, the intravesical device comprises a housing configured forintravesical insertion; and a dosage form comprising a chemotherapeuticagent, wherein the housing holds the dosage form and is configured torelease the chemotherapeutic agent in an amount effective for thetreatment of tumor metastasis or tumor at a site distinct from thebladder in an individual having a urothelial carcinoma of lower tract.In some embodiments, the intravesical drug delivery device comprises ahousing which contains and controllably releases the chemotherapeuticagent and is elastically deformable between a retention shape configuredto retain the device in the individual's bladder and a deployment shapefor passage of the device through the individual's urethra. In someembodiments, the device comprises a drug reservoir lumen bounded by afirst wall (such as a cylindrical wall) and a second wall (such as adisc shaped wall), wherein the first wall is impermeable to the drug andthe second wall is permeable to the chemotherapeutic agent. In someother embodiments in which the first wall is impermeable to thechemotherapeutic agent and the second wall is permeable to thechemotherapeutic agent, the first wall and the second wall are adjacentone another and together form an annular tube defining the drugreservoir lumen. In some of these embodiments, the second wall is in theform of a strip extending at least a portion of the length of the firstwall structure. In some embodiments, the device comprises at least twodrug reservoir lumens, and in some embodiments each reservoir comprisesa different drug contained within. In some embodiments, thechemotherapeutic agent is delivered by a device that delivers thechemotherapeutic agent in pulses. Such pulsed, staged, or intermittentdosing may be achieved by various intravesical device designs. In someembodiments, different doses of drug may be provided in separatereservoirs each configured to provide release of drug at a predefinedtime in vivo, for example with the use of multiple apertures each havingits own associated degradable timing membrane, as described in U.S.Publication 2010/0331770 and U.S. Publication 2017/0157360, which areincorporated herein by reference.

The chemotherapeutic agent may be released from the device by osmoticpressure or by diffusion, depending on the desirable drug releaseprofile. In some embodiments, the chemotherapeutic agent (such asgemcitabine) contained in the housing is in a non-liquid form, such as anon-liquid form is selected from the group consisting of tablets,granules, pellets, semisolids, powders, capsules, and combinationsthereof. Various non-liquid forms of drug cores are further describedherein.

In some embodiments, the chemotherapeutic agent is delivered from thedevice via passive transport. In some embodiments, passive transport isfacilitated transport.

The individual described herein can be a mammal, preferably a human. Insome embodiments, the individual is unsuitable for systemicchemotherapy. In some embodiments, the individual has a compromisedimmune system. In some embodiments, the individual is resistant to orunsuitable for chemotherapeutic therapy. In some embodiments, theindividual is resistant to or unsuitable for other cancer immunotherapy.In some embodiments, the individual has a low neutrophil count. In someembodiments, the individual is ineligible for cisplatin-basedcombination therapy. In some embodiments, the individual has notreceived prior radiation therapy to the urinary bladder. In someembodiments, the individual is unwilling or unable to undergo acystectomy. In some embodiments, the individual may undergo a cystectomyfollowing treatment with the chemotherapeutic agent.

The effectiveness of the methods described herein can be assessed byvarious methods. For example, for methods of tumor treatment, theeffectiveness of the method can be evaluated by tumor growth or tumorshrinkage at a second tumor site distinct from a first site in thebladder of an individual. In some embodiment, the effectiveness of themethod is evaluated based on the level of one or more markers. Forexample, the effectiveness of the method can be determined based on thelevels of TGF-beta or IL-10 of an individual. In some embodiment, theeffectiveness of the method is evaluated based on the number of animmune cell population. For example, the effectiveness of the method canbe determined based on the levels of regulatory T cells in a secondtumor site distinct from a first site in the bladder of an individual.In some embodiments, the level of CD4+ (helper) T cells can be measured.In some embodiments, the level of CD8+ (cytotoxic) T cells can bemeasured. In some embodiments, the number of immune cells are measuredin the spleen. In some embodiment, the effectiveness of the method isevaluated based on tumor volume in a second tumor site distinct from afirst site in the bladder of an individual. In some embodiment, theeffectiveness of the method is evaluated based on the number ofcirculating tumor cells in an individual. In some embodiments, theeffectiveness of the methods can be evaluated based on the ratio of thechemotherapeutic agent and its metabolic product in the urine. Forexample, when the chemotherapeutic agent is gemcitabine, theeffectiveness of the method may be evaluated based on the ratio ofchemotherapeutic agent (e.g., gemcitabine) and its metabolite (e.g.,dFdU) in the urine. For cancer treatment, a ratio below a thresholdvalue may be indicative of effectiveness.

For example, provided herein is a method of treating a tumor at adistant at a site distinct from the bladder in an individual having aurothelial carcinoma of lower tract, comprising locally delivering tothe bladder an effective amount of a chemotherapeutic agent, wherein thechemotherapeutic agent is delivered continuously to the bladder for atleast about 24 hours, wherein the level of one or more cytokinesindicative of an immune response is altered upon treatment. In someembodiments, the level of the cytokine during treatment is alteredcompared to the level prior to treatment. In some embodiments, the levelof the cytokine following treatment is altered compared to the levelprior to treatment. In some embodiments, the level of a cytokine ismodified in an individual who has received treatment compared to anindividual who has not received treatment. In some embodiments, thelevel of systemic TGF-β is reduced during or following treatment with achemotherapeutic agent such as gemcitabine. In some embodiments, thelevel of TGF-β is reduced 2, 3, 4, 5, 6, 7, or 10 fold followingtreatment with the chemotherapeutic agent. In some embodiments, thelevel of systemic IL-10 is increased during or following treatment witha chemotherapeutic agent, such as gemcitabine. In some embodiments, thelevel of IL-10 is increased 1, 2, 3, 4, 5, 6, 7, or 10 fold during orfollowing treatment with a chemotherapeutic agent such as gemcitabine.In some embodiments, the level of TNF-α is increased during or followingtreatment with a chemotherapeutic agent, such as gemcitabine. In someembodiments, the level of TNF-α is increased 1, 2, 3, 4, 5, 6, 7, or 10fold during or following treatment with a chemotherapeutic agent such asgemcitabine.

In some embodiments, the methods provided herein comprise locallydelivering to the bladder an effective amount of a chemotherapeuticagent, wherein the chemotherapeutic agent is delivered continuously tothe bladder for at least about 24 hours, and measuring the level of oneor more cytokines. In some embodiments, the level of IL-10 is measured.In some embodiments, the level of TGF-β is measured. In someembodiments, the level of TNF-α is measured. In some embodiments, thecirculating level of a cytokine is measured. In some embodiments, thesplenic level of a cytokine is measured. In some embodiments, the levelof a cytokine in peripheral blood, serum, or plasma is measured. In someembodiments, the level of a cytokine is measured using an ELISA, flowcytometry, or radioimmunoassay.

Provided herein is a method of treating a tumor at a distant at a sitedistinct from the bladder in an individual having a urothelial carcinomaof lower tract, comprising locally delivering to the bladder aneffective amount of a chemotherapeutic agent, wherein thechemotherapeutic agent is delivered continuously to the bladder for atleast about 24 hours, wherein the level of an immune cell type ismodified upon treatment. In some embodiments the level of an immune celltype is modified during treatment as compared to prior to treatment. Insome embodiments, the level of an immune cell type is modified followingtreatment compared to prior to treatment. In some embodiments, the levelof an immune cell type is modified in an individual who has been treatedcomparison to an individual who has not been treated. In someembodiments, the level of an immune cell type in the spleen is modified.In some embodiments, the level of an immune cell type in a peripheralblood sample is modified. In some embodiments, the level of activatedhelper T cells, such as CD4+/CD25+ cells, is increased during orfollowing intravesicular treatment with a chemotherapeutic agent, suchas gemcitabine. In some embodiments the level of activated cytotoxic Tcells, such as CD8+/CD25+ cells, is increased during or followingintravesicular treatment with a chemotherapeutic agent, such asgemcitabine. In some embodiments, the level of regulatory T cells, suchas CD4+/FOXP3+ and/or CD8+FOXP3+, cells is increased during or followingintravesicular treatment with a chemotherapeutic agent, such asgemcitabine.

In some embodiments, the methods provided herein comprise locallydelivering to the bladder an effective amount of a chemotherapeuticagent, wherein the chemotherapeutic agent is delivered continuously tothe bladder for at least about 24 hours, and measuring the level of oneor more immune cell populations. In some embodiments, the number ofactivated helper T cells, such as CD4+/CD25+ cells is measured. In someembodiments, the number of activated cytotoxic T cells, such asCD8+/CD25+ cells, is measured. In some embodiments, the number ofregulatory T cells, such as CD4+/FOXP3+ and/or CD8+FOXP3+ is measured.In some embodiments, the number of a population of immune cells ismeasured in the spleen. In some embodiments, the number of a populationof immune cells is measured in peripheral blood. In some embodiments,the number of a population of immune cells is measured by FACS.

In some embodiments, the present invention provided herein furthercomprises radiation therapy. In some embodiments, the chemotherapeuticagent (such as gemcitabine) is delivered in a neoadjuvant setting. Insome embodiments, the chemotherapeutic agent is delivered in an adjuvantsetting. In some embodiments, the method further comprises a thirdtherapy comprising surgery, and the delivery of the chemotherapeuticagent to the individual can be initiated at the time of the surgery,prior to the surgery, or after the surgery. In some embodiments, thedelivery of the chemotherapeutic agent to the individual is initiatedduring a cystoscopy.

A. Patient Populations

The present invention in one aspect provides a method of inhibitingtumor cell growth at a second tumor site distinct from a first tumorsite in the bladder of an individual. The methods provided herein areuseful for treatment of a range of individuals having bladder cancer. Insome embodiments, the individual has a urothelial carcinoma of the lowertract. In some embodiments the individual has a squamous carcinoma,sarcomatoid, or small cell carcinoma in the bladder. In someembodiments, the individual has a histologically variant subtype of aurothelial carcinoma of the lower tract, such as pappilary,micropapillary, or carcinoma in situ. In some embodiments, theindividual has an infiltrating urothelial carcinoma of lower tract suchas a transitional cell carcinoma (e.g. micropappliary or spindle cell),a lymphopithelial carcinoma, a schmincke tumor, or a giant cellcarcinoma. In some embodiments the individual has a non-invasiveurothelial neoplasia such as a transitional cell carcinoma in situ, anon-invasive pappilary transitional cell carcinoma, a papillarytransitional cell neoplasm of low malignant potential, or a urothelialpapilloma. In some embodiments, the individual has a squamous neoplasm,such as a squamous cell carcinoma, a verrucous carcinoma, or a squamouscell papilloma. In some embodiments, the individual has a glandularneoplasm, such as an adenocarcinoma or a villous adenoma.

In some embodiments, the individual has previously undergonechemotherapy. In some embodiments, the individual is ineligible forimmunomodulatory therapy.

In some embodiments, the individual is not eligible for neoadjuvantcisplatin-based therapy comprising administering a chemotherapeutic(such as gemcitabine) locally to the bladder. In some embodiments, theindividual refuses neoadjuvant cisplatin-based therapy comprisingadministering a chemotherapeutic agent (such as gemcitabine) locally tothe bladder. In some embodiments, the individual would receive radicalcystectomy but is ineligible for cisplatin-based neoadjuvant therapy.

In some embodiments, the individual is ineligible for cisplatin-basedtherapy based upon co-morbidities including poor performance status,poor renal function, hearing loss, peripheral neuropathy, and cardiacdisease. In some embodiments, the individual is ineligible forcisplatin-based therapy based upon the absence of one or more high-riskfeatures such as lymphovascular invasion (LVI), hydronephrosis, andconcomitant carcinoma in situ (CIS).

In some embodiments, the individual is unfit or not eligible for acystectomy. In some embodiments, the individual is ineligible forradical cystectomy under the National Comprehensive Cancer Network(NCCN) guidelines. For example, the individual is unfit for curativetherapy due to frailty. Prior to the present methods, such individualstypically received palliative radiation without chemotherapy (3.5Gy/fraction—10 treatments; or 7 Gy/fraction—7 treatments; TURBT; or notreatment). In some embodiments, the individual is unfit forplatinum-based chemotherapy. In some embodiments, chemotherapy prior toradiation therapy is not recommended for the individual. In someembodiments, the individual does not receive curative therapy orsystemic chemotherapy. In some embodiments, the individual has cT2-cT3disease.

In some embodiments, the individual cannot tolerate radical cystectomybased upon the American Society of Anesthesiology (ASA) guidelines. Forexample, the individual who cannot tolerate radial cystectomy may bedeemed medically unfit for surgery requiring general or epiduralanesthesia.

In other embodiments, the individual lacks operative post-operative careinfrastructure or personnel as determined by the Comprehensive GeriatricAssessment provided by the American Society of Anesthesiologists. Underthese guidelines, an individual is deemed frail if he or she showsabnormal independent activities of daily living, severe malnutrition,cognitive impairment, or comorbidities cumulative illness rating scalefor geriatrics (CISR-G) grades 3-4. Furthermore, under currentguidelines, subjects must be deemed unfit for radical cystectomy (RC)due to comorbid conditions with a risk of mortality ≥5% as estimated bythe American College of Surgeons risk calculator using the currentprocedure terminology code 51595 or 51596 for cystectomy.

In some embodiments, the bladder cancer is resected prior toadministration of the chemotherapeutic agent (such as gemcitabine). Insome embodiments, the individual undergoes a TURBT prior toadministration of the chemotherapeutic agent (such as gemcitabine) tothe bladder. In some embodiments, the tumor is maximally resected priorto administration of the gemcitabine such that no visible tumor ispresent. In some embodiments, the tumor is non-maximally resected priorto administration of the gemcitabine. In some embodiments, the tumor isnon-maximally resected prior to administration of the gemcitabine suchthat residual tumor is present. In some embodiments, the patient is T0after TURBT.

In some embodiments, the individual has undergone TURBT and has residualtumor at the site of resection, wherein the amount of residual tumor issufficient to provide a tumor antigen to elicit an immune response. Insome embodiments, about ½, ⅓, ¼, ⅕, ⅙, 1/7, ⅛, 1/9, 1/10, 1/20, 1/50,1/100 of the original tumor amount remains after TURBT. In someembodiments at least ½, ⅓, ¼, ⅕, ⅙, 1/7, ⅛, 1/9, 1/10, 1/20, 1/50, 1/100of the original tumor amount remains after TURBT. In some embodiments,the individual has stage Ta, Tis, T1, T2, T2a, T2b, T3, T3a, T4, T4a, orT4b cancer following TURBT. In some embodiments, a sufficient amount ofresidual tumor is an amount sufficient to elicit an immune response at asite distinct from the bladder. The elicitation of an immune responsecan be determined by the increase/decrease of a cytokine (such as IL-10,TGFβ, or INFγ) or the population of immune cells (such as regulatory Tcells, activated CD4+T helper cells, or activated CD8+ cytotoxic Tcells) as described above.

The present invention also has the advantage of being useful forindividuals who are not eligible for a systemic chemotherapy or hormonetherapy. In some embodiments, the individual is eligible for a systemicchemotherapy or hormone therapy, but elect not to have a systemicchemotherapy or hormone therapy. In some embodiments, the individual isin the elderly, relatively frail population (such as above 70 years). Insome embodiments, the individual is at least 60, 65, 70, 75, 80, 85 or90 years old. In some embodiments, the individual is about 20 to 60years old.

The present invention also has the advantage of being useful forindividuals who have bladder cancer and are not eligible for a radiationtherapy. In some embodiments, the individual is eligible for a radiationtherapy, but elects not to have a radiation therapy. In someembodiments, the individual does not receive radiation therapy.

B. Dosage Regimens

The following section describes various aspects (embodiments) of dosingand treatment regimens, any and all of which apply to the methodsdescribed herein.

In some embodiments, there is provided a method of treating tumormetastasis at a site distinct from the bladder in an individual having atumor in the bladder comprising a) a first phase of local and continuousdelivery of a chemotherapeutic agent (gemcitabine) to the bladder; b) arest period; and c) a second phase of local and continuous delivery ofthe same chemotherapeutic agent to the bladder. In some embodiments, theconcentration of the chemotherapeutic agent or active metabolite thereofin the plasma of the individual is at a subtherapeutic level during thedelivery period.

In some embodiments, there is provided a method of treating tumormetastasis at a site distinct from the bladder in an individual having atumor in the bladder comprising administering a chemotherapeutic agent(gemcitabine) to the bladder continuously for at least 3 weeks. In someembodiments, the chemotherapeutic agent (gemcitabine) is administeredlocally to the bladder for about 12 weeks.

In some embodiments, the concentration of chemotherapeutic agent in theurine of the individual is less about 0.1 μg/mL during the rest period.

In some embodiments, the dosage or release rate of the chemotherapeuticagent during the different delivery periods may be the same ordifferent. For example, in some embodiments, the chemotherapeutic agent(such as gemcitabine) is delivered continuously over at least a month,wherein the chemotherapeutic agent delivery period is at least one day,and wherein the interval between the chemotherapeutic agent (such asgemcitabine) delivery period is no more than about a week. In someembodiments, the method comprises: a) a first chemotherapeutic agent(such as gemcitabine) delivery period (such as 7 days), wherein theconcentration of chemotherapeutic agent in the urine of the individualis at least about 0.1 μg/mL; b) a rest period (such as 14 days); and c)a second delivery of the same chemotherapeutic agent (such asgemcitabine) for a time period (such as 7 days), wherein theconcentration of chemotherapeutic agent in the urine of the individualis greater than about 0.1 μg/mL. In some of these embodiments, the firstchemotherapeutic agent delivery period is seven days, the rest period isfourteen days, and the second chemotherapeutic agent delivery period isseven days. In some embodiments, the chemotherapeutic agent is deliveredon days 1-7 and days 21-28 of a treatment regimen. In some embodiments,the chemotherapeutic agent is delivered on days 1-14 and 22-34. In someembodiments, the chemotherapeutic agent is delivered on days 1-6, 1-5,or 1-4 and days 21-27, 21-26 or 21-25. In some embodiments, thechemotherapeutic agent is delivered on days 1-14 and 28-41. In someembodiments, the concentration of the chemotherapeutic agent or activemetabolite thereof in the plasma of the individual is at asubtherapeutic level during the delivery period.

In some of embodiments, the first and second delivery periods are boththree weeks. In some embodiments, the first and second delivery periodsare both 14-21 days. In some embodiments, the first and second deliveryperiods are both 14 days. In some embodiments, the chemotherapeuticagent is delivered multiple times over a period of six weeks. In someembodiments, the chemotherapeutic agent is delivered multiple times overa period of 12 weeks. In some embodiments, the chemotherapeutic agent isdelivered for four times for about each 14 days over a period of 12weeks.

The chemotherapeutic agent in some embodiments is continuously deliveredinto the bladder for a specific time period. For example, in someembodiments, the chemotherapeutic agent is continuously delivered to thebladder for at least about 24 hours (such as at least about 2, 3, 4, 5,6, 7, 8, 9, 10, 15, 20, 25, or 30 days). In some embodiments, thechemotherapeutic agent is continuously delivered to the bladder forabout 1, 2, 3, 4, 5, 6, or 7 days.

In some embodiments, the chemotherapeutic agent may be continuouslydelivered for about 24 hours or more by delivering repeated shorterdoses. For example, the chemotherapeutic agent may be deliveredrepeatedly at intervals of about 1, 2, 5, 10, 20, or 30 minutes over thecourse of about 24 hours or more. In some of these embodiments, thechemotherapeutic agent can be delivered using an electronic device topump the agent into the bladder at regular intervals. For example, anexternal pump operably connecting a fluid drug source and atransurethral catheter having a distal end deployed into theindividual's bladder can be programmed to provide intermittent or pulseddelivery of the chemotherapeutic agent.

It may be advantageous to continuously deliver the chemotherapeuticagent locally to the bladder more than once. For example, in someembodiments, the chemotherapeutic agent is delivered locally to thebladder of an individual at least twice, at least 3 times, at least 4times, at least 5 times, or at least 10 times. In some embodiments,chemotherapeutic agent is delivered multiple times over a period of atleast 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, atleast 6 weeks, at least 8 weeks, or at least 12 weeks. In someembodiments, the chemotherapeutic agent is delivered multiple times overa period of at least 1 month, at least 2 months, at least 3 months, atleast 4 months, at least 5 months, at least 6 months, at least 12months, or at least 18 months. For example, in some embodiments,chemotherapeutic agent is delivered locally to the bladder of anindividual twice, 3 times, 4 times, 5 times, or 10 times. In someembodiments, chemotherapeutic agent is delivered multiple times over aperiod of one month, one month to 18 months, 2 months to 18 months, 3months to 18 months, one month to 6 months, or one month to two months.In some embodiments, the chemotherapeutic agent is delivered locally tothe bladder 4 times. In some of these embodiments, the chemotherapeuticagent is delivered locally to the bladder of the individual 4 times,wherein each chemotherapeutic agent delivery period is 3 weeks. In someof these embodiments, the chemotherapeutic agent is delivered locally tothe bladder of the individual 4 times, wherein each chemotherapeuticagent delivery period is 2 weeks.

In some embodiments, the chemotherapeutic agent is delivered locally tothe bladder of the individual for about 12 weeks. In some embodiments,the first delivery period is about 12 weeks. In some embodiments, themethod comprises a first delivery period of about 12 weeks followed byone or more additional delivery periods, each separated by rest periodsof about 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7months, 8 months, 9 months, 10 months, 11 months, or 12 months). In someembodiments the chemotherapeutic agent is delivered annually, forexample during a maintenance phase.

In some embodiments, the chemotherapeutic agent is continuouslydelivered multiple times over at least one month, wherein eachchemotherapeutic agent delivery period is at least one day. In someembodiments, chemotherapeutic agent is delivered at least twice over aperiod of at least one month. In some embodiments, chemotherapeuticagent is delivered at least three times over a period of at least onemonth. In some embodiments, a chemotherapeutic agent is delivered atleast four times over a period of at least two months. In someembodiments, the interval between each delivery period ofchemotherapeutic agent (rest period) is no more than about 4 weeks, nomore than about 3 weeks, no more than about 2 weeks, or no more thanabout one week. In some embodiments, a chemotherapeutic agent isdelivered over a least one month, wherein each delivery period ofchemotherapeutic agent is at least one day, and wherein the intervalbetween each delivery period (rest period) is no more than about oneweek. In some embodiments, the interval between each delivery period(rest period) is about 3 to 50 days, 3 to 30 days, 5 to 20 days or 8 to15 days. In some embodiments the rest period is up to about 4 months(for example 1 month, 2, months, 3 months, or 4 months).

In some embodiments, the method comprises (i) placing a chemotherapeuticagent releasing intravesical device into the bladder of the individual,wherein the device remains in the bladder for 7 days and wherein thegemcitabine is continuously delivered to the bladder. In someembodiments, provided herein is a method of treating muscle invasivebladder cancer in an individual comprising (i) placing achemotherapeutic agent releasing intravesical device into the bladder ofthe individual, wherein the device remains in the bladder for 7 days andwherein the chemotherapeutic agent releasing intravesical devicedelivers the chemotherapeutic agent passively. In some embodiments,provided herein is a method of treating muscle invasive bladder cancerin an individual comprising (i) placing a first chemotherapeutic agentreleasing intravesical device into the bladder of the individual on day0, (ii) removing the first chemotherapeutic agent releasing intravesicaldevice at day 7, (iii) placing a second chemotherapeutic agent releasingintravesical device in the bladder of the individual at day 21, and (iv)removing the second chemotherapeutic agent releasing intravesical deviceat day 28. In some of these embodiments, the chemotherapeutic agent isgemcitabine and one or both of the first and second chemotherapeuticagent releasing intravesical devices contain 225 mg of gemcitabinebefore placement into the bladder. In some embodiments, theconcentration of the chemotherapeutic agent or active metabolite thereofin the plasma of the individual is at a subtherapeutic level during thedelivery period.

In some embodiments, the method comprises (i) placing a chemotherapyreleasing intravesical device into the bladder of the individual,wherein the device remains in the bladder for 21 days and wherein thegemcitabine is continuously delivered to the bladder. In someembodiments, provided herein is a method of treating muscle invasivebladder cancer in an individual comprising (i) placing achemotherapeutic agent releasing intravesical device into the bladder ofthe individual, wherein the device remains in the bladder for 21 daysand wherein the chemotherapeutic agent releasing intravesical devicedelivers the chemotherapeutic agent passively. In some embodiments,provided herein is a method of treating muscle invasive bladder cancerin an individual comprising (i) placing a first chemotherapeutic agentreleasing intravesical device into the bladder of the individual on day0, (ii) removing the first chemotherapeutic agent releasing intravesicaldevice at day 21, (iii) placing a second chemotherapeutic agentreleasing intravesical device in the bladder of the individual at day21, and (iv) removing the second chemotherapeutic agent releasingintravesical device at day 42. In some of these embodiments, thechemotherapeutic agent is gemcitabine and one or both of the first andsecond chemotherapeutic agent releasing intravesical devices contain 225mg of gemcitabine before placement into the bladder. In someembodiments, the concentration of the chemotherapeutic agent or activemetabolite thereof in the plasma of the individual is at asubtherapeutic level during the delivery period.

The chemotherapeutic agent may be delivered at a single release rate, orat different release rates at different time points. For example, insome embodiments, the chemotherapeutic agent is delivered in a firstphase of the delivery at a first release rate followed by a second phaseof the delivery having a second release rate. In some embodiments, thefirst release rate is faster (such as at least 2×, 3×, 4×, 5×, or 10×faster) than the second release rate. In some embodiments, the firstrate is slower (such as at least 2×, 3×, 4×, 5×, or 10× slower) than thesecond release rate.

In some embodiments, the method comprises a first chemotherapeutic agentdelivery period which a first dose is used in an induction period and asecond chemotherapeutic agent delivery period in which a second dose(i.e., booster dosage) is used in a maintenance period. In someembodiments, the first dose (prime dosage) is different from the seconddose (booster dosage).

In some embodiments, the chemotherapeutic agent is delivered at a dose(i.e., release rate) of from about 1 mg/day to about 300 mg/day, such asany of about 1 mg/day to about 5 mg/day, about 5 mg/day to about 10mg/day, about 10 mg/day to about 50 mg/day, about 50 mg/day to about 100mg/day, about 100 mg/day to about 225 mg/day (e.g., about 140 mg, about160 mg, about 180 mg, about 200 mg, or about 220 mg) or about 200 mg/dayto about 300 mg/day. In some embodiments, about 100 mg to about 500 mgof gemcitabine is delivered to the individual. In some embodiments,about 100 mg to about 200 mg of gemcitabine is delivered to theindividual. In some embodiments, about 160 mg of gemcitabine isdelivered to the individual over seven days. In some embodiments, about100 mg to about 200 mg of gemcitabine is delivered to the individualover 7 days. In some embodiments, about 200 mg to about 225 mg ofgemcitabine is delivered to the individual over 21 days. In someembodiment, about 225 mg of chemotherapeutic agent is delivered to theindividual over 21 days. In some embodiments, 225 mg of gemcitabine isadministered to the individual over seven days. In some embodiments, 225mg of gemcitabine is administered to the individual over 21 days.

In some embodiments, the concentration of the chemotherapeutic agent(such as gemcitabine) in the urine during the delivery period is about0.1 μg/mL to about 200 μg/mL, such as about any of 0-0.5, 0.5-1, 1-2,2-3, 3-4, 4-5, 5-6, 6-7, 7-8, 8-9, 9-10, 10-20, 20-30, 30-40, 40-60,60-80, 80-100, 100-150, or 150-200 μg/mL. In some embodiments, thechemotherapeutic agent concentration in the plasma of the individualduring the period of continuous delivery is less than about 1 μg/mL,such as less than about any of 0.5, 0.4, 0.3, 0.2, 0.1, 0.05, 0.04,0.03, 0.02, or 0.01 μg/mL. In some embodiments, the concentration of thechemotherapeutic agent or active metabolite thereof in the plasma of theindividual is at a subtherapeutic level during the delivery period. Insome embodiments, upon delivery of chemotherapeutic agent the ratio ofchemotherapeutic agent in the urine to chemotherapeutic agent in theplasma of the individual during the period of continuous delivery isgreater than about 500:1. In some of these embodiments, thechemotherapeutic agent is gemcitabine. In some embodiments, the plasmaconcentration of dFdU is less than 0.3 μg/mL upon delivery of thechemotherapeutic agent. In some embodiments, the plasma concentration ofdFdU is less than 0.2 μg/mL upon delivery of the gemcitabine. In someembodiments the plasma concentration of dFdU is less than 0.1 μg/mL upondelivery of the chemotherapeutic agent. In some embodiments, the plasmaconcentration of dFdU is between 0.1 and 0.3 μg/mL upon delivery of thegemcitabine.

Intravesical Devices Device Shape

In some embodiments, the methods provided herein comprise administeringa chemotherapeutic agent (such as gemcitabine) using an intravesicaldevice. In some embodiments, the intravesical device comprises adeployment shape and a retention shape. For example, the device may beelastically deformable between a relatively straightened or uncoiledshape suited for insertion through a lumen (e.g., the urethra) into thebladder of the individual (the deployment shape) and a retention shapesuited to retain the device within the bladder. For the purposes of thisdisclosure, terms such as “relatively expanded shape,” “relativelyhigher-profile shape,” or “retention shape” generally denote any shapesuited for retaining the device in the intended implantation location,including but not limited to a pretzel shape or other coiled shape(e.g., comprising bi-oval or overlapping coils) that is suited forretaining the device in the bladder. The retention shape provides thatthe device resists becoming entrained in urine and excreted when theindividual voids. Similarly, terms such as “relatively lower-profileshape” or “deployment shape” generally denote any shape suited fordeploying the drug delivery device into the body, for example thebladder, including, but not limited to, including a linear or elongatedshape that is suited for deploying the device through the workingchannel of catheter, cystoscope, or other deployment instrumentpositioned in the urethra. In embodiments, the drug delivery device maynaturally assume the relatively expanded shape and may be deformed,either manually or with the aid of an external apparatus, into therelatively lower-profile shape for insertion into the body. For example,the external apparatus may be an inserter configured for transurethralinsertion. Once deployed the intravesical device may spontaneously ornaturally return to the initial, relatively expanded shape for retentionin the body. In some embodiments, the device behaves like a spring,deforming in response to a compressive load (e.g., deforming the deviceinto a deployment shape) but spontaneously returning to a retentionshape once the load is removed.

In some embodiments, the shape changing functionality of theintravesical device described in the preceding paragraph may be providedby including a shape retention frame (i.e., a “retention frame”) in thedevice, such as those disclosed in published applicationsUS2012/0203203, US2013/0158675, US2015/0360012, US20150165177,US2015/0165178, US20160199544, WO2014/145638, WO2015200752, andWO2011/031855, which are incorporated herein by reference. In someembodiments, the device may include a retention frame lumen in which theretention frame, which may be an elastic wire, e.g., a superelasticalloy such as nitinol, is secured. The retention frame may be configuredto return spontaneously to a retention shape, such as a “pretzel” shapeor another coiled shape, such as those disclosed in the applicationspreviously incorporated. In particular, the retention frame may retainthe device in the body, such as in the bladder. The retention shapeprovides that the device resists becoming entrained in urine andexcreted when the individual voids. For example, the retention frame mayhave an elastic limit and modulus that allows the device to beintroduced into the body in a relatively lower-profile shape, permitsthe device to return to the relatively expanded shape once inside thebody, and impedes the device from assuming the relatively lower-profileshape within the body in response to expected forces, such as thehydrodynamic forces associated with contraction of the detrusor muscleand urination. Thus, the device may be retained in the individual'sbladder once deployed, limiting or preventing accidental expulsion.

In some other embodiments, the shape changing functionality of theintravesical device may be provided by forming the device housing atleast in part of a thermally shape set elastic polymer.

The material used to form the device body (i.e., the housing), at leastin part, may be elastic or flexible to permit moving the device betweendeployment and retention shapes. When the device is in the retentionshape, the retention frame portion may tend to lie inside the drugreservoir portion, although the retention frame portion can bepositioned inside, outside, above, or below the drug reservoir portionin other cases. The material used to form the device body may be waterpermeable so that solubilizing fluid (e.g., urine) can enter the drugreservoir portion to solubilize the non-liquid forms of thechemotherapeutic agent, immunomodulating agent, additional therapeuticagent, functional agent, or combination thereof contained in the drugreservoir once the device is deployed into the bladder. For example,silicone or another biocompatible elastomeric material may be used. Inother embodiments, the device body may be formed, at least in part, of awater-impermeable material.

In some embodiments, the device body is made of an elastic,biocompatible polymeric material. The material may be non-resorbable orresorbable. Example non-resorbable materials include synthetic polymersselected from poly(ethers), poly(acrylates), poly(methacrylates),poly(vinyl pyrolidones), poly(vinyl acetates), poly(urethanes),celluloses, cellulose acetates, poly(siloxanes), poly(ethylene),poly(tetrafluoroethylene) and other fluorinated polymers, andpoly(siloxanes). Example resorbable materials, specificallybiodegradable or bioerodible polymers, include synthetic polymersselected from poly(amides), poly(esters), poly(ester amides),poly(anhydrides), poly(orthoesters), polyphosphazenes, pseudo poly(aminoacids), poly(glycerol-sebacate), poly(lactic acids), poly(glycolicacids), poly(lactic-co-glycolic acids), poly(caprolactones),poly(caprolactone) (PC) derivatives, amino alcohol-based poly(esteramides) (PEA) and poly(octane-diol citrate) (POC), and other curablebioresorbable elastomers. PC-based polymers may require additionalcross-linking agents such as lysine diisocyanate or2,2-bis(e-caprolacton-4-yl)propane to obtain elastomeric properties.Copolymers, mixtures, and combinations of the above materials also maybe employed.

In some embodiments, the device body comprises silicone, thermoplasticpolyurethane, ethyl vinyl acetate (EVA), or a combination thereof. Insome embodiments, the device body comprises two different thermoplasticmaterials, one of which is a hydrophilic thermoplastic polyurethane andis drug permeable, with the other being drug-impermeable. The drugimpermeable material may be a selected from the group consisting ofhydrophilic polyurethane, hydrophilic polyesters, and hydrophilicpolyamides. The device body may comprise an annular tube formed by anextrusion or coextrusion process, using one or more these materials, asdescribed in U.S. Publication 2016/0310715, which is incorporated hereinby reference.

Drug Core

In embodiments in which the chemotherapeutic agent is delivered from anintravesical drug delivery device, the drug may be housed in the devicein various forms, which may depend on the particular mechanism by whichthe device controllably releases the drug into fluid (e.g., urine) inthe bladder. In some embodiments, the drug is provided in a solid,semi-solid, or other non-liquid form, which advantageously mayfacilitate stable storage of the drug before the device is used andadvantageously may enable the drug payload of the device to be stored insmaller volume than would be possible if the drug were housed in theform of a liquid solution. In some embodiments, the non-liquid form isselected from tablets, granules, pellets, powders, semisolids (e.g., anointment, cream, paste, or gel), capsules, and combinations thereof. Inone embodiment, the drug is in the form of a plurality of tablets, suchas mini-tablets described in U.S. Pat. No. 8,343,516.

For example, the chemotherapeutic agent, may take such forms assuspensions, solutions, or emulsions in oily or aqueous vehicles, andmay contain formulatory agents such as suspending, stabilizing and/ordispersing agents. Alternatively, the active ingredients may be inpowder form, obtained by aseptic isolation of sterile solid or bylyophilization from solution, for constitution with a suitable vehicle,e.g., sterile, pyrogen-free water, before use.

In one embodiment, the chemotherapeutic agent (such as gemcitabine) isformulated with one or more excipients that include a viscosityenhancing agent to control release of solubilized chemotherapeutic agent(such as gemcitabine) from a release aperture in the device housing. Inanother embodiment, the device reservoir includes both thechemotherapeutic agent and a viscosity enhancing agent, but they are notco-formulated and instead are provide in discrete regions within thereservoir, e.g., as separate tablets. Suitable viscosity enhancingagents, including but not limited to polyethylene oxide (PEO), are knownin the pharmaceutical arts. In some variations of the embodiment, theviscosity enhancing agent may be provided, e.g., formulated, with ureaor another osmotic agent.

In one embodiment, the chemotherapeutic agent is administered to theindividual with a solubility enhancing agent. In an embodiment, thesolubility enhancing agent is urea. In one embodiment, the urea isprovided in a tablet or other solid form and loaded with thechemotherapeutic agent in the drug reservoir of an intravesical drugdelivery device. The urea may also function, depending on the device, asan osmotic agent to facilitate generation of an osmotic pressure in adrug reservoir. In a particular embodiment, the chemotherapeutic agentand the osmotic agent are configured as separate tablets (or other solidforms) positioned within different regions of the drug reservoir asdescribed in PCT WO 2015/026813 (Lee et al.) which is incorporated byreference herein.

In some embodiments, the device may comprise a drug reservoir lumen. Insome of these embodiments, each drug reservoir lumen may hold one orseveral drug tablets or other solid drug units. In one embodiment, thedevice holds from about 10 to 100 cylindrical drug tablets, such asmini-tablets, among a number of discrete drug reservoir lumens. Incertain embodiments, the mini-tablets may each have a diameter of about1.0 to about 3.3 mm, such as about 1.5 to about 3.1 mm, and a length ofabout 1.5 to about 4.7 mm, such as about 2.0 to about 4.5 mm.

Drug Housing

The release of chemotherapeutic agent from the intravesical devicesdescribed herein may be driven and controlled by different mechanisms ofaction. In various embodiments, the drug may be released from theintravesical drug delivery device by diffusion through a wall of thedrug housing, by diffusion through one or more defined apertures in awall of the drug housing, by osmotic pressure through an aperture in thedrug housing, by osmotic pressure through one or more transiently formedmicrochannels, by erosion of a drug formulation in contact with urine inthe bladder, or by a combination thereof. In some embodiments, drugrelease is controlled by drug diffusion through a drug-permeable polymeror matrix component defining part of the device housing. In oneembodiment, the device includes a drug-permeable polymer component.

The size of the housing, including the thickness of the wall, may beselected based on the volume of drug (and functional agent, if any)formulation(s) to be contained, the desired rate of delivery of the drugfrom the device body/housing, the intended site of implantation of thedevice within the body, the desired mechanical integrity for the device,the desired release rate or permeability to water and urine, the desiredinduction time before onset of initial release, and the desired methodor route of insertion into the body, among other factors. In embodimentsin which the housing is a tube, the tube wall thickness may bedetermined based on the mechanical properties and water permeability ofthe tube material, as a tube wall that is too thin may not havesufficient mechanical integrity while a tube wall that is too thick mayexperience an undesirably long induction time for initial drug releasefrom the device and/or may not have sufficient flexibility to permitdelivery through a urethra or other narrow body lumen.

In some embodiments, the housing may include an elongated, annular tubehaving an inner diameter from about 2 mm to about 5 mm. The drug, andfunctional agent if any, may be solid tablets having a diametersubstantially the same as the inner diameter of the elongated annulartube. In some embodiments, the housing holds one or more first units(e.g., tablets) comprising a drug and one or more second units (e.g.,tablets) comprising a functional agent which facilitates release of thedrug. One or more of the first unit tablets may fill a length from about1 cm to about 3 cm of the lumen of the tube, and one or more of thesecond unit tablets may fill a length from about 10 cm to about 15 cm ofthe lumen of the tube. In one embodiment, the ratio of volume of thefirst unit(s) to volume of the second unit(s) is from about 0.05 toabout 0.5. Other lengths and ratios of the tablet payloads areenvisioned.

In some embodiments, the housing may be an elongated, annular tubehaving a wall thickness from 0.1 to 0.4 mm, such as a wall thickness of0.2 mm. The housing material may comprise one or more biocompatibleelastomers. The housing material may be selected such that the housinghas a durometer from 25 A to 80 A, such as 25 A, 50 A, 65 A, 70 A, or 80A.

In various embodiments, the intravesical device may release the drugcontinuously or intermittently to achieve a concentration of the drug inthe bladder that produces a sustained, therapeutically effectiveconcentration of the drug in urine in the bladder as described in themethods provided herein. In certain embodiments, the intravesical devicemay release the chemotherapeutic agent in an amount of from 1 mg/day to1000 mg/day, for example from 20 mg/day to 300 mg/day or from 25 mg/dayto 300 mg/day. In certain embodiments, these release rates are providedover a treatment period as described herein. In certain embodiments,these release rates are provided over a treatment period from 14 days to21 days.

Osmotic and Diffusion Systems

Following in vivo deployment, the device releases the drug. Release mayoccur, as described above, due to an osmotic pressure gradient betweenthe interior and exterior of the device, the drug passing through one ormore orifices or passing pores in the device under the force of osmoticpressure. Release may also occur by diffusion, whereby the drug passesthrough one or more orifices or passing pores in the device and/orthrough a drug-permeable wall of the device, due to a drug concentrationgradient between the interior and exterior of the device. Combinationsof these release modes within a single device are possible, and in someembodiments are preferred in order to achieve an overall drug releaseprofile not readily achievable from either mode individual.

In some embodiments in which the device comprises a drug in a solidform, elution of drug from the device occurs following dissolution ofthe drug within the device. Bodily fluid enters the device, contacts thedrug and solubilizes the drug, and thereafter the dissolved drugdiffuses from the device or flows from the device under osmotic pressureor via diffusion. This “dissolved drug” may include micro- and nanoscaleparticulates of the drug in suspension that remain following substantialdissolution of the solid form of the drug and are also able to bereleased from the device, e.g., through an aperture in the devicehousing. For example, the drug may be solubilized upon contact withurine in the bladder. In certain embodiments, a water permeable wallportion of the housing is permeable to the drug in aqueous solution,such that solubilized drug is released via the wall portion, alsoreferred to herein as “trans-wall diffusion.” After the device isdeployed in the individual's bladder, urine permeates through the wall,enters the reservoir, and solubilizes the chemotherapeutic agent, andthe functional agent if present. In some embodiments, the drug thendiffuses directly through the wall at a controlled rate, due to a drugconcentration gradient between the interior and the exterior of thedevice. For example, the housing and/or any water or drug permeable wallportions may be silicone, a thermoplastic polyurethane,ethylene-co-vinyl acetate (EVA), or a combination thereof.

In some embodiments, the intravesical device may contain a unitconcentration of 225 mg of gemcitabine. In some of these embodiments,the device may be configured to deliver about 100 to about 225 mg ofgemcitabine (e.g., about 140 mg, about 160 mg, about 180 mg, about 200mg, or about 220 mg) mg of chemotherapeutic agent to the individual overa 7 day period or over a 3 week period.

In a particular embodiment, the drug delivery device may include apermeation system as described in WO2014/145638 and U.S. Publication2016/0310715, which are herein both incorporated by reference in itsentirety. In some embodiments, the drug delivery device includes ahousing having a closed drug reservoir lumen bounded by a first wallstructure and a hydrophilic second wall structure; and a drugformulation comprising chemotherapeutic agent contained in the drugreservoir lumen, wherein the first wall structure is permeable orimpermeable to water and impermeable to the drug, and the second wallstructure is permeable to the chemotherapeutic agent.

In some embodiments, the device housing has walls bounding and definingthe drug reservoir of the device that are made of a first material thatserves as the first wall structure and a second material that serves asthe second wall structure, such that drug release occurs essentiallyonly through the second material. In one embodiment, the device does notinclude an aperture; drug release is only by diffusion through thesecond wall structure. As used herein, the terms “impermeable to thedrug” and “impermeable to water” refer to the wall structure beingsubstantially impermeable to the drug or to water, such that essentiallyno drug or water is released via the wall structure over the therapeuticrelease period. For use in the bladder, it is desirable that the devicebe compliant (i.e., easily flexed, soft feeling) during detrusor musclecontraction in order to avoid or mitigate discomfort and irritation tothe patient. Thus, the durometer of the first and second materials ofconstruction are a design consideration, and the proportion of a highdurometer material may be limited in constructing a device housing of agiven size while keeping it suitably compliant in the bladder. Forexample, Tecophilic™ thermoplastic polyurethane (Lubrizol Corp.) mayhave a Shore hardness greater than 70 A, such as from 80 A to 65 D,while silicone tubing which may have a Shore hardness of from 50 A to 70A. Accordingly, it can be advantageous to utilize the combination ofthese two different polymeric materials, rather than making the deviceentirely of the water-swelling hydrophilic, drug-permeable secondmaterial.

The arrangement of the first and second wall structures can take avariety of forms. In certain embodiments, the first wall structure is acylindrical tube and the second wall structure is an end wall disposedat least one end of the cylindrical tube, or the first wall structureand the second wall structure are adjacent one another and together forma cylindrical tube. That is, drug release is controlled by drugdiffusion through a drug-permeable component defining a portion of theclosed device housing. The drug-permeable wall structure may be located,dimensioned, and have material properties to provide the desired rate ofcontrolled drug diffusion from the device. In one embodiment, the drugpermeable wall may include a disk stabilized in the lumen of a tube ator near an end of the tube, optionally sandwiched between an innerwasher and an outer washer. In another embodiment, the drug permeablewall is part of a sidewall of a tubular housing, or part of an end pluglocated at the end of a tubular housing.

The length and width, e.g., wall portion formed of the water permeablematerial are selected to provide a desired rate of water flux into thereservoir defined by device housing. In one embodiment, the width of thewater permeable wall portion may be quantified by the arc angle definingthe wall when viewed in cross-section normal to the luminal axis. Thewater permeable region(s) of the device housing can be controlled togive a selected area of, and thus rate for, osmotic water imbibition,and yet advantageously maintain suitable overall dimensions andelasticity of the device, formed of suitable biocompatible elastomers.Advantageously by forming the device housing by a co-extrusion process,the structural variations of the water permeable region(s) can becreated with conventional co-extrusion equipment by selection of theprocessing parameters, thereby beneficially providing the ability tocost-effectively manufacture multiple structural device configurations.In some embodiments, the length of the water permeable regions(s) runsalong only a portion of the overall length of the device. In such anembodiment, larger arc angles of the water permeable region(s) cantherefore be employed while keeping the rate of drug release at adesirable level over an extend period of time.

In some embodiments, the wall may have a varied thickness over thecircumference of the wall, for example the drug permeable portion mayhave a thickness that is less than the thickness of the drug impermeableportion. Moreover, the thinner drug permeable wall structure may bedisposed at various positions relative the adjacent, thicker drugimpermeable wall structure. In some embodiments, drug release iscontrolled by drug diffusion through a drug-permeable component defininga portion of the closed device housing. The drug-permeable wallstructure may be located, dimensioned, and have material properties toprovide the desired rate of controlled drug diffusion from the device.

In some embodiments, the drug delivery device comprises a housingcomprising a first wall structure and a second wall structure that areadjacent one another and together form a tube defining a drug reservoirlumen; and a drug contained in the drug reservoir lumen, wherein: (i)the second wall structure, or both the first wall structure and thesecond wall structure, are permeable to water, (ii) the first wallstructure is impermeable to the drug and the second wall structure ispermeable to the drug, such that the drug is releasable in vivo bydiffusion through the second wall structure, (iii) the second wallstructure comprises less than 90 percent of a cross sectional area ofthe tube, in a cross section normal to the longitudinal axis of thetube, (iv) and the first wall structure comprises a first polyurethanecomposition.

In some embodiments, the device comprises an elongated, elastic housinghaving a drug reservoir lumen extending between a first closed end and asecond closed end; and a drug contained in the drug reservoir lumen,wherein (i) the housing comprises a tubular wall structure whichcomprises: a first annular segment formed entirely of a first materialwhich is impermeable to the drug, and a second annular segment formed atleast partially of a second material which is permeable to the drug andconfigured to release the drug in vivo by diffusion through the secondmaterial in the second annular segment, and (ii) the first annularsegment has a first end which is integrally formed and connected with afirst end of the second annular segment.

In some embodiments, the walls that define the drug reservoir lumens mayhave varying thickness. Housings with walls of different thicknesses mayimprove the housing's flexibility, compressibility, or both. Differentwall thicknesses also may aid in securing a solid drug unit in the drugreservoir lumens.

In some embodiments, the intravesical device body, or housing, mayinclude openings (e.g., at the opposed ends of an annular tube) in needof sealing following loading of the drug reservoir with the drugpayload, during the assembly process. Any of these defined openings orends of the housings, including the monolithic housing and modularhousing units, may be sealed, if desired to close off an opening. Thissealing may be accomplished with a sealing substance or structure. Thesealing structure may be formed of biocompatible material, including ametal such as stainless steel, a polymer such as silicone, a ceramic, orsapphire, or adhesive, among others or combinations thereof. The sealingsubstance or structure may be biodegradable or bioerodible. In oneembodiment, a medical grade silicone adhesive or other adhesive isloaded into the opening in a fluid or workable form and then cure withinthe housing opening to seal it. In some embodiments, the housingincludes one or more predefined apertures for release of the drug fromthe device. These drug-release apertures are not the defined openingswhich are sealed. In other embodiments, the housing does not include apredefined drug-release aperture.

In some embodiments the device releases drug without a predefined drugrelease aperture (i.e., orifice). Release of drug from a device withouta predefined drug-release aperture may be driven by diffusion or osmoticpressure. Examples of such suitable “no-orifice” release systems aredescribed in PCT Patent Application Publication No. WO 2014/144066 (TB130) and U.S. Patent Application Publication No. 2014/0276636 (TB 134),which are incorporated herein by reference.

In some embodiments, the drug delivery device includes an osmotic systemas described in U.S. Publication 2016/0199544, U.S. Pat. No. 8,679,094,and U.S. Publication 2016/0008271, which are herein incorporated byreference.

In some embodiments, the device comprises a housing defining areservoir; a first unit contained within the reservoir, the first unitcomprising a drug; and a second unit contained within the reservoir in aposition distinct from the first unit, wherein the second unit comprisesa functional agent that facilitates in vivo release of the drug fromhousing. In some embodiments, the first unit comprises one or more solidtablets which comprise at least one drug (e.g., a chemotherapeuticagent, such as gemcitabine), and the second unit comprises one or moresolid tablets (e.g., which comprise an osmotic agent, such as urea). Insome embodiments, the housing is in the form of an elongated elastomerictube having a lumen (i.e., the reservoir) in which all of the solidtablets of the first and second units are aligned and contained. Thediameter of the solid tablets may be substantially the same as thediameter of the lumen.

When osmotic release is the desired drug release mode, the functionalagent in the second units may include an osmotic agent that facilitatesosmotic release of the drug. For example, the osmotic agent may have ahigher solubility than the drug, such that the osmotic agent expeditessolubilization and/or subsequent release of the drug. This beneficiallyallows for the delivery of low solubility or other drugs typically onlydelivered via diffusion, from osmotic delivery-based devices. The devicemay exhibit an induction period while a sufficient volume of functionalagent and/or drug are solubilized to achieve the osmotic pressuregradient.

Subsequently, the device may exhibit a zero-order release rate for anextended period, followed by a reduced, non-zero-order release rate overa decay period. A desired delivery rate can be achieved bycontrolling/selecting various parameters of the device, including butnot limited to the surface area and thickness of the water permeablewall; the permeability to water of the material used to form the wall;the shape, size, number and placement of the apertures; and thedissolution profiles of the drug and functional agent.

The devices described herein may also be configured to release drug viadiffusion, alone or in combination with osmotic release. The device maybe configured to allow the solubilized drug to pass through a portion ofthe housing or one or more apertures therein.

Alternatively, or in combination with a water permeable wall portion,the housing may include at least one aperture configured to permit afluid to enter the reservoir in vivo. The housing may also include oneor more apertures or passing pores configured to permit solubilized drugto pass there through.

In some embodiments of the osmotic system, the device housing includes afirst elastomeric material that is water permeable and a secondelastomeric material that is water impermeable, wherein both materialsare selected to be impermeable to the drug contained in the housing.

FIGS. 5A-5C illustrate one embodiment of an intravesical device usefulin the methods described herein. The device 100 includes a drugreservoir portion 102 and a retention frame portion 104. In FIG. 5A, thedevice 100 is shown in a relatively expanded shape suited for retentionwithin the urinary bladder of an individual. In FIG. 5C, the device 100is shown in a relatively lower-profile shape for deployment through theworking channel 202 of a deployment instrument 200, such as a cystoscopeor other catheter, e.g., for insertion into and through the urethra andinto the bladder of the patient. Following deployment (release of thedevice) into the bladder, the device 100 may assume the relativelyexpanded shape to retain the drug delivery device in the bladder. In theillustrated embodiment, the drug reservoir and retention frame portions102, 104 of the drug delivery device 100 are longitudinally aligned andare integrally formed or otherwise coupled to each other along theirlength.

The drug delivery device 100 includes an elastic or flexible device body106 that defines a drug reservoir lumen 108 and a retention frame lumen110. The drug reservoir lumen 108 is configured to house a drug (e.g., achemotherapeutic agent) which is in the form of a plurality of soliddrug units 112, to form the drug reservoir portion 102. Interstices 116or breaks formed between adjacent drug units 112 permit the drug units112 to move with reference to each other so that the device 100 isflexible despite being loaded with drug in solid form. The retentionframe lumen 110 is configured to house a retention frame 114 to form theretention frame portion 104.

As shown in the cross-sectional view of FIG. 5B, the device body 106includes a tube or wall 122 that defines the drug reservoir lumen 108and a tube or wall 124 that defines the retention frame lumen 110. Thetubes 122, 124 and lumens 108, 110 can be substantially cylindrical,with the drug reservoir lumen 108 having a relatively larger diameterthan the retention frame lumen 110, although other configurations can beselected based on, for example, the amount of drug to be delivered, thediameter of the retention frame, and deployment considerations such asthe inner diameter of the deployment instrument. The device body 106 maybe formed integrally, such as via molding or extrusion, althoughseparate construction and assembly of the tubes 122, 124 is possible.The wall 124 that defines the retention frame lumen 110 may extend alongthe entire length of the wall 122 that defines the drug reservoir lumen108, so that the retention frame lumen 110 has the same length as thedrug reservoir lumen 108 as shown, although one wall may be shorter thanthe other wall in other embodiments. Further, the two walls 122, 124 areattached along the entire length of the device in the illustratedembodiment, although intermittent attachment can be employed.

As shown in FIG. 5A, the drug reservoir lumen 108 is loaded with anumber of drug units 112 in a serial arrangement. For example, betweenabout 10 and about 100 drug units 112 may be loaded, such as betweenabout 20 and about 80 drug units 112. The drug units may, for example,be tablets, beads, or capsules. Essentially any number of drug units maybe used, depending upon the sizes of the reservoir and the drug units.The drug reservoir lumen 108 includes open ends 130 and 132, which areshown as relatively circular openings at opposite ends of the drugreservoir lumen 108. At least one of the openings provides ingress forthe drug units 112 to be placed into the drug reservoir lumen 108 duringdevice loading and assembly.

End plugs 120 block openings 130 and 132 following loading of the drugunits 112. The end plugs 120 may be cylindrical and may be secured inthe drug reservoir lumen 108 by frictional engagement and/or an adhesiveor other fastening means. Each end plug 120 includes an aperture 118, asillustrated, to provide a passageway for releasing drug from the drugreservoir lumen 108. In some alternative embodiments, only one of theend plugs includes an aperture. In some other alternative embodiments,neither of the end plugs includes an aperture, and in some of thoseembodiments, the tube wall 122 includes a defined aperture for releaseof drug therethrough.

The retention frame lumen 110 is loaded with the retention frame 114,which may be an elastic wire, such as a nitinol wire, (thermally)shape-set into the overlapping coiled shape shown in FIG. 5A. Theretention frame 114 may have an elastic limit and modulus that allowsthe device 100 to be introduced into the body in a relativelylower-profile shape, permits the device 100 to return the relativelyexpanded shape once inside the body, and impedes the device fromassuming the relatively lower-profile shape within the body in responseto expected forces, such as the hydrodynamic forces associated withcontraction of the detrusor muscle and urination.

Erosion-Based Systems

In some embodiments, which may be used with tablets comprisinglow-solubility drugs, the drug is provided in tablet form secured in thedevice with exposed tablet faces, such that release of drug from thedevice occurs by controlled erosion/dissolution, as described in U.S.Pat. No. 9,107,816. In some embodiments, the device may comprise modularhousings. The modular housings are typically formed from at least twoseparate housing units, each unit housing at least one solid drug unit.The material from which each housing unit is formed defines at least onedrug reservoir lumen capable of housing a solid drug unit. The drugreservoir lumens may have one or more defined openings. For example, thedrug reservoir lumen may have two opposed openings which exposecorrespondingly opposed end surfaces of the at least one solid drug unithoused therein. In certain embodiments, the at least two separatehousing units in the modular housings are connected, directly orindirectly, by a retention frame. In some embodiments, the modularhousing units may be placed on the retention frame to form a “bracelet”design. The devices may have one housing unit or a plurality of housingunits. The number of housing units may be limited only by the size ofthe retention frame by which they are connected.

In some embodiments, one or more of the separate housing units includesa retention frame lumen through which a shared retention frame isextended. In certain embodiments, the retention frame lumen and the drugreservoir lumen of each housing unit are arranged parallel to eachother. In particular embodiments, the retention frame lumen and the drugreservoir lumen of each housing unit are arranged perpendicular to eachother. In further embodiments, the retention frame lumen and the drugreservoir lumen of each housing unit are arranged at an angle other than0° (parallel) and 90° (perpendicular), such as 5, 10, 30, 45, 60, or85°. In further embodiments, the devices described herein include two ormore housing units with at least two of the following configurations:(1) the retention frame lumen and drug reservoir lumen are arrangedsubstantially parallel to each other, (2) the retention frame lumen anddrug reservoir lumen are arranged substantially perpendicular to eachother, and (3) the retention frame lumen and drug reservoir lumen arearranged at an angle other than 0° (parallel) and 90° (perpendicular).

Integrated Silicone-Drug Delivery Systems

In some embodiments, the device may comprise an elastic polymer-drugmatrix as described in WO2015/200752, which is herein incorporated byreference in its entirety.

Devices with Multiple Release Portions

In some embodiments, the device includes at least two drug releaseportions, at least one release portion releasing drug at a differentrate than another release portion as described in WO2011/031855 which isherein incorporated by reference in its entirety. The release portionsmay achieve different release rates by having different configurations,by housing different drug formulations, or by employing differentrelease mechanisms, among others or combinations thereof. The releaseportions may be combined to achieve a desired release profile. Forexample, the device may include release portions that exhibit differentinduction or lag times before the onset of initial release, that releasedrug at different rates or according to different release curves afterthe onset of release, or that release drug for different periods beforethe drug load is substantially exhausted, among others or combinationsthereof. The disparate release portions may be combined to achieve adesired release profile from the drug delivery device as a whole, suchas a release profile that demonstrates a relatively short initial lagtime and thereafter demonstrates continued release at a relativelyconstant rate over an extended period.

In some embodiments, the devices are loaded with drugs in the form of anumber of solid drug tablets, which may be smaller in size thanconventional drug tablets. Because the devices control release of thedrug into the body, the drug itself may include little or no excipientsthat control drug release. Instead, the excipients present in the drugtablets may be present primarily or completely to facilitate thetableting process or solubilization in vivo. Thus, the devices mayprovide a high drug payload on a volume or weight basis, yet the devicesmay be small enough for in vivo deployment in a minimally invasivemanner.

The drug housing also permits the egress of drug, in either liquid orsemi-solid form as implanted or following in vivo solubilization. Thewall may be formed from a drug-permeable material that permits drugefflux through the drug housing along its entire length. The wall alsomay be formed from a material that is semi-permeable to the drugdepending at least in part on the drug form. For example, the wall maybe permeable to the drug in one form, such as a charged form, but notanother form, such as uncharged form (e.g., base form versus salt form).The wall also may include one or more openings or passageways formedcompletely through it that permit drug to exit the drug housing.

The drug housing may house a drug in the form of a number of solid drugtablets, which are aligned within the drug housing in a serialarrangement and are enclosed within the drug housing with sealingstructures, such as plugs, that close entry openings on opposite ends ofthe drug housing. Interstices or breaks formed between adjacent drugtablets permit the drug tablets to move with reference to each other sothat the device is flexible despite being loaded with drug in solidform.

The drug portion can have any combination of the characteristics orconfigurations described herein, meaning the aperture may be provided,omitted, substituted with a passing pore, or augmented with additionalapertures or passing pores; the housing may have a porous wall with anopen-cell structure or a closed-cell structure; one or more degradabletiming structures or release modulating structures may be associatedwith the housing, or any combination thereof.

The drug tablets may be aligned in any arrangement other than a serialarrangement, depending on the configuration of the drug housing. Thedrug tablets may fill any portion of the drug housing other than theentire drug housing as illustrated. A filling material such as siliconeadhesive can be used to fill any portion of the drug housing that is notloaded with drug tablets, or air may be used, increasing the buoyancy ofthe device. The composition of the drug tablets may be the same or mayvary along the device. The drug also may be in forms other than a drugtablet, such as other liquid, semi-solid, or solid forms (e.g.,granules).

In particular embodiments, the drug delivery device includes at leasttwo discrete or segregated drug portions associated with a singleretention portion. The drug portions may be separate drug housings eachassociated with the retention portion, or the drug portions may beseparate areas within a single drug housing that is associated with theretention portion.

Each drug portion may be defined by a portion of the wall of the drughousing and at least one partition structure, which separates the drugportion from a second drug portion. The partition structure may be aplug inserted into the housing, such as a cylinder, sphere, or disk,among others, which is secured in place due to its size or with anadhesive. The partition structure also may be a portion of the housingformed directly therein, such as by molding.

A device with at least two discrete portions may be suited forcontrolled release of at least two drug payloads from a correspondingnumber of drug reservoirs. The two discrete portions may have the sameconfigurations or different configurations as described herein. The twodrug payloads may be the same as each other or may differ from eachother with reference to content, such as active ingredient content orexcipient content; form, such as salt form or base form; state, such asliquid, semi-solid, or solid state; among others or combinationsthereof. Thus, the two discrete portions may release the two drugpayloads at the same time or at different times, at the same rate or atdifferent rates, via the same release mechanisms or different releasemechanisms, or any combination thereof.

For example, one drug portion may be configured to release its drugpayload relatively quickly after implantation and another drug portionmay be configured to experience an induction time before beginningrelease, or a combination thereof. The onset of release of two payloadsin different drug portions can be staged. Examples of quick release drugportions include a drug portion that operates as a relativelyfast-acting osmotic pump, such as a silicone tube having a relativelythinner wall, a drug portion that is loaded with drug in a quick releaseform, such as liquid form or a specially formulated solid form, a drugportion associated with a relatively fast-acting degradable timingstructure, or combinations thereof. Thus, the device may release drugduring an initial, acute phase and during a maintenance phase.

As another example, one drug portion may be configured to release itsdrug payload at a relatively faster rate than the other drug payload.For example, one drug portion may house a drug payload with low watersolubility for diffusive release that is initiated relatively soon afterimplantation, and another drug portion may house a drug payload that ishighly water soluble for osmotic release after an induction period. Asanother example, one drug portion may house a drug payload in a liquidstate for quick release through an aperture having a fast-actingdegradable timing membrane, and another drug portion may house anotherdrug payload of solid tablets for slow release following solubilizationin vivo. As still another example, one drug portion may have arelatively solid wall while another drug portion may have a number ofapertures or pores formed through its wall, which may increase therelease rate due to diffusion, or a closed-cell porous wall, which mayincrease the release rate due to increased permeation of water or drugthrough the wall.

The release portions may be combined to achieve a desired releaseprofile. For example, the device may include release portions thatexhibit different induction or lag times before the onset of initialrelease, that release drug at different rates or according to differentrelease curves after the onset of release, or that release drug fordifferent periods before the drug load is substantially exhausted, amongothers or combinations thereof. The disparate release portions may becombined to achieve a desired release profile from the drug deliverydevice as a whole, such as a release profile that demonstrates arelatively short initial lag time and thereafter demonstrates continuedrelease at a relatively constant rate over an extended period.

By combining multiple distinct drug portions in a single device, thedevice may exhibit a desired release profile of a chemotherapeuticagent. The release profile from the device as a whole may be the sum ofthe release profiles of the discrete portions, for example, with thefirst portion exhibiting minimal lag time before the onset of release,the second portion exhibiting a short induction period as the osmoticpressure gradient develops, and the third portion exhibiting a longerdelay before onset as the degradable structure dissolves or degrades.Once release begins from any one portion, the release rate may berelatively zero-order for an extended period, followed by a period ofdecay. It should be noted that the three discrete portions are examples,and that any number or combination of discrete portions may be used toachieve the desired release profile.

Because the different drug portions are merely segregated areas withinin a single tubular housing, the device advantageously may be relativelysimple to construct and deploy, and yet the different drug portionsexhibit different release profiles due to the different drug payloads,aperture placement, and degradable timing structures. In otherembodiments in which the drug portions use, for example, walls ofdifferent materials, thicknesses, or porous cell structures, the housingmay vary along its length or separate drug housings may be used. Thus,controlled release may be achieved in a range of manners.

Gels

In another embodiment, a coating substance may be intravesically appliedto the bladder wall (e.g., to an area of the urothelium inside theurinary bladder), wherein the coating substance includes thechemotherapeutic agent or other drug and one or more excipient materialsthat promote adherence of the coating substance to the bladder wall andprovides continuous controlled release of the drug over the treatmentperiod. The coating substance may be a mucoadhesive formulation, such asgels, ointments, creams, pastes, films, emulsion gels, tablets,polymers, or a combination thereof. Mucoadhesive formulation polymersmay include hydrogels or hydrophilic polymers, polycarbophil (i.e.Carbopols, etc.), chitosan, polyvinylpyrrolidone (PVP), lectin,polyethyleneglycolated polymers, celluloses, or a combination thereof.Suitable celluloses include methyl cellulose (MC), carboxymethylcellulose (CMC), hydroxypropyl cellulose (HPC), or combinations thereof.The coating substance may include a permeation enhancer. Non-limitingexamples of permeation enhancers include dimethyl sulfoxide (DMSO),sodium carboxymethyl cellulose (NaCMC), lipids, surfactants, orcombinations thereof. A coating substance may be deployed in the bladderso that the coating substance engages the bladder wall.

The coating substance may be deployed in the bladder using a deploymentinstrument. The deployment instrument may be any device designed tonavigate natural lumens of the body to reach the intended implantationsite. For deployment in the bladder, the deployment instrument is sizedand shaped for passing through a urethra of a patient to a bladder. Thedeployment instrument may be a known device, such as a catheter orcystoscope, or a specially designed device. The deployment instrument isused to deploy the coating substance into the body and is subsequentlyremoved from the body, leaving the coating substance wholly implanted inthe body. Once so implanted, the coating substance may release drug intothe body for an extended period. A comparable procedure can be used todeploy any of the devices or drugs described herein into other parts ofthe body through other natural lumens. For example, a deploymentinstrument can be used to deploy a liquid drug or drug formulation intothe bladder by passing the deployment instrument through a urethra.

EXEMPLARY EMBODIMENTS

Embodiment 1. A method of treating or suppressing tumor metastasis at asite distinct from the bladder in an individual having a urothelialcarcinoma of lower tract, comprising locally delivering to the bladderan effective amount of a chemotherapeutic agent, wherein thechemotherapeutic agent is delivered continuously to the bladder for atleast about 24 hours.

Embodiment 2. The method of embodiment 1, wherein the tumor metastaticsite is at one or more of: liver, lung, bone, brain, lymph node, pelvicnode, peritoneum, skin, prostate, breast, colon, rectum, and cervix.

Embodiment 3. The method of any one of embodiments 1-2, wherein thetumor metastasis is at two or more different sites.

Embodiment 4. A method of inhibiting tumor cell growth at a second tumorsite distinct from a first tumor site in the bladder of an individual,comprising locally delivering to the bladder an effective amount of achemotherapeutic agent, wherein the chemotherapeutic agent is deliveredcontinuously to the bladder for at least about 24 hours.

Embodiment 5. The method of embodiment 4, wherein the tumor cells at thesecond tumor site are located at a pelvic node.

Embodiment 6. The method of embodiment 4, wherein the tumor cells at thesecond tumor site are located at a distant node.

Embodiment 7. The method of embodiment 4, wherein the tumor cells at thesecond tumor site are circulating tumor cells.

Embodiment 8. The method embodiment 4, wherein the tumor cells at thefirst tumor site result from metastasis of a primary tumor at the secondtumor site.

Embodiment 9. The method of embodiment 8, wherein the tumor cells at thesecond site are selected from the group consisting of liver, lung, bone,brain, lymph node, pelvic node, peritoneum, skin, prostate, breast,colon, rectum, and cervix.

Embodiment 10. The method of any one of embodiments 4-9, wherein theindividual has a urothelial carcinoma of lower tract.

Embodiment 11. The method of any one of embodiments 1-10, wherein theindividual has bladder cancer.

Embodiment 12. The method of embodiment 11, wherein the individual hasmuscle invasive bladder cancer or carcinoma in situ (CIS).

Embodiment 13. The method of embodiment 11 or 12, wherein the individualis unfit for or refuses cystectomy.

Embodiment 14. The method of any one of embodiment 11-13, wherein theindividual has not undergone transurethral resection of bladder tumors(TURBT).

Embodiment 15. The method of any one of embodiments 11-13, wherein theindividual has undergone transurethral resection of bladder tumors(TURBT).

Embodiment 16. The method of embodiment 15, wherein the individual hasresidual tumor at the site of resection.

Embodiment 17. The method of any one of embodiments 1-16, wherein thechemotherapeutic agent is delivered continuously to the bladder of theindividual for a period of about 7 days to about three weeks.

Embodiment 18. The method of any one of embodiments claims 1-17, whereinthe method comprises an induction delivery period followed by amaintenance delivery period.

Embodiment 19. The method of embodiment 18, wherein the inductiondelivery period and the maintenance delivery period are separated by arest period of about 7 to about 14 days.

Embodiment 20. The method of embodiment 18, wherein the chemotherapeuticagent is delivered at a first release rate during the induction deliveryperiod followed and a second release rate during the maintenancedelivery period.

Embodiment 21. The method of any of embodiments 1-20, wherein thechemotherapeutic agent is delivered at a dose of from about 1 mg/day toabout 300 mg/day.

Embodiment 22. The method of any of embodiments 1-21, wherein theconcentration of the chemotherapeutic agent in the urine is from about0.1 μg/mL to about 200 μg/mL during the delivery period.

Embodiment 23. The method any one of embodiments 1-22, comprising

-   -   a) an induction delivery period, wherein the concentration of        chemotherapeutic agent in the urine of the individual is at        least about 0.1 μg/mL;    -   b) a rest period; and    -   c) a maintenance delivery period, wherein the concentration of        the chemotherapeutic agent in the urine of the individual is        greater than about 0.1 μg/mL.

Embodiment 24. The method of any of embodiments 1-23, wherein theindividual does not receive a radiation therapy.

Embodiment 25. The method of any one of embodiments 1-24, wherein themethod further comprises a radiation therapy.

Embodiment 26. The method of any one of embodiments 1-25, wherein thechemotherapeutic agent is delivered by an intravesical delivery device.

Embodiment 27. The method of embodiment 26, wherein the intravesicaldevice contains 100 mg to 500 mg of the chemotherapeutic agent.

Embodiment 28. The method of any of embodiment 26-27, wherein theintravesical device comprises a housing configured for intravesicalinsertion; and a dosage form comprising chemotherapeutic agent, whereinthe housing holds the dosage form and is configured to releasechemotherapeutic agent.

Embodiment 29. The method of any one of embodiments 26-28, wherein theintravesical drug delivery device comprises:

-   -   a housing defining a reservoir;    -   a first unit contained within the reservoir, the first unit        comprising an chemotherapeutic agent; and    -   a second unit contained within the reservoir in a position        distinct from the first unit, wherein the second unit comprises        a functional agent that facilitates in vivo release of the        chemotherapeutic agent from the housing.

Embodiment 30. The method of any one of embodiments 26-29, wherein theintravesical drug delivery device comprises a housing which contains andcontrollably releases the chemotherapeutic agent and is elasticallydeformable between a retention shape configured to retain the device inthe individual's bladder and a deployment shape for passage of thedevice through the individual's urethra.

Embodiment 31. The method of any one of embodiments 26-30, wherein thedevice comprises a drug reservoir lumen bounded by a first wall and asecond wall, wherein the first wall is impermeable to the drug and thesecond wall is permeable to the chemotherapeutic agent.

Embodiment 32. The method of any one of embodiments 26-31 wherein thechemotherapeutic agent is released from the device by osmotic pressure.

Embodiment 33. The method of any one of embodiments 26-31, wherein thechemotherapeutic agent is released from the device by diffusion.

Embodiment 34. The method of any of embodiments 22-29, wherein thechemotherapeutic agent contained in the housing is in a non-liquid form.

Embodiment 35. The method of embodiment 34, wherein the non-liquid formis selected from the group consisting of tablets, granules, powders,semisolids, capsules, and combinations thereof.

Embodiment 36. The method of any one of embodiments 1-35, wherein thechemotherapeutic agent is selected from the group consisting of anucleoside analog, a taxane, a platinum-based agent, and ananthracycline analogue.

Embodiment 37. The method of any one of embodiments 1-36, wherein thechemotherapeutic agent is a nucleoside analog.

Embodiment 38. The method of embodiment 37, wherein the nucleosideanalog is gemcitabine.

Embodiment 39. The method of any one of embodiments 1-38, wherein theindividual is human.

Embodiment 40. The method of any one of embodiments 1-39, wherein theindividual is unsuitable for systemic chemotherapy.

Embodiment 41. The method of any one of embodiments 1-40, wherein theindividual has a compromised immune system.

Embodiment 42. The method of any one of embodiments 1-41, wherein theindividual has a high tumor burden.

EXAMPLES Example 1

Standardized bladder perfusion system was modified to introduce bladderand subcutaneous tumors. The bladders were first surgically cannulatedby placing a catheter into the bladder, fixed in place using a suture,the free end exteriorized between the scapulae.

The animals were allowed to heal. Bladder tumors were established byinjecting tumor cell suspension directly into bladder wall. Subcutaneoustumor was established by injecting tumor cell suspension under skinabdominal flank.

The bladder and flank tumor model used in this study utilizedimmunocompetent Wistar rats, 7 to 8 weeks in age and weighing between150 to 200 g. The bladders were first surgically cannulated by placing aP50 catheter into the bladder dome which was fixed in place using apurse string suture and the free end exteriorized between the scapulae.See FIG. 1. Upon recovery, the animals were able to freely move about intheir cages and their health status was monitored daily. Per studyprotocol, different groups of bladder cannulated rats were nextinoculated with NBTII tumor cells (Nara Bladder Tumor No. 2; ATCC®CRL1655™). This is a rat syngeneic bladder tumor cell line originallyderived from tumors induced with N-butyl-N-(4-hydroxybutyl) nitrosamine.In certain treatment groups, the tumor cells were injected directly intothe bladder wall as a 50 uL cell suspension of approximately 2×10⁶cells. In these treatment groups and in a control group which did notreceive the bladder tumor inoculation, a tumor cell suspension ofapproximately 50 uL containing approximately 2.5×10⁶ was also injectedsubcutaneously into the abdominal flank.

The study consisted of four treatment groups as shown in FIG. 2.

Group 1 (NoIVC SCT Only, N=5) animals were inoculated with NBTII tumorcells subcutaneously only in the abdominal flank on study Day 0. Nobladder cannulation procedure was performed.

Group 2 (Control, N=10) animal bladders were cannulated on study Day 0.On study Day 17, NBTII tumor cells were inoculated subcutaneously intothe abdominal flank. Phosphate buffered saline was perfused via thecannula into the bladder beginning on study Day 6 at a constant rate of0.3 mL per hour for 5 days and again beginning on Day 20 for anadditional 5 day treatment period.

Group 3 (SCT after BT, N=10) animal bladders were cannulated on studyDay 0 and on study Day 4 the bladders were inoculated with NBTII tumorcells. On study Day 17, the animals were also inoculated,subcutaneously, with NBTII tumor cells into the abdominal flank.Gemcitabine HCl in PBS (180 ug/mL) was perfused into the bladder via thebladder cannula beginning on study Day 6 at a constant rate of 0.3 mLper hour for 5 days and again beginning on Day 20 for an additional 5day treatment period.

Group 4 (SCT with BT, N=10) animal bladders were cannulated on study Day0 and on study Day 4 both the bladder and abdominal flank wereinoculated with NBTII tumor cells. Gemcitabine HCl in PBS (180 ug/mL)was perfused via the cannula into the bladder beginning on study Day 6at a constant rate of 0.3 mL per hour for 5 days and again beginning onDay 20 for an additional 5 day treatment period.

Subcutaneous tumor volumes were serially measured post inoculation everytwo or three days using a caliper method.

The results of this study are summarized in FIGS. 3 and 4. In the Group1 animals inoculated with only subcutaneous NBTII tumors in theabdominal flank, the tumor implantation rate was 100% which was the ratefor all treatment groups. Following an initial rapid growth phase, thetumors grew at a relatively constant rate over the duration of thestudy. The tumor doubling rate was approximately 6 to 10 days. Incomparison, subcutaneous flank tumors inoculated on study Day 17,following bladder cannulation, bladder tumor inoculation and 5 days ofintravesical phosphate buffered saline perfusion were observed to growat a very similar rate to that observed in Group 1. The similar growthrates demonstrate bladder cannulation, intravesical vehicle perfusionand the presence of a bladder tumor had no effect on the growthcharacteristics of the subcutaneous tumor.

In contrast, intravesical gemcitabine perfusion over two 5-day treatmentcycles exhibited dramatic and unexpected effects on subcutaneous tumorgrowth when bladder and subcutaneous tumors were inoculated on Day 4 orwhen the subcutaneous tumor inoculation was delayed to study Day 17. Inthe Group 4 animals with both bladder and subcutaneous tumors implantedon Day 4, the subcutaneous tumors were observed to initially grow asexpected. Unexpectedly, the tumor growth dramatically slowed or fullyarrested in the animals by the end of the first intravesical perfusionperiod. Over the following 7-day drug free period, all subcutaneoustumors failed to return to their initial growth rate or show anyevidence of increased growth rate. Also, unexpectedly, retreatment ofthe bladder tumor with a second 5-day intravesical gemcitabine treatmentresulted in a rapid decline of tumor volume until all but one tumor wasundetectable by palpation.

In the Group 3 animals where subcutaneous tumors were implanted on studyDay 17, 14 days after bladder tumor inoculation and following the first5-day intravesical gemcitabine perfusion period, initiation of thesecond gemcitabine 5 day perfusion unexpectedly resulted in a strikingand immediate decline of subcutaneous tumor volume. The decline in tumorvolume continued during the 5-day intravesical gemcitabine perfusionuntil all subcutaneous tumors were undetectable by palpation.

Standard intravesical gemcitabine treatments are typically prepared as40 mg/mL instillations (2000 mg gemcitabine in 50 mL water). Theperfusate concentrations used in this study are approximately 200-foldlower. Similarly, the total daily bladder exposure is over 1000-foldlower. Prior studies in animals and humans have shown low concentrationsof intravesical gemcitabine do not produce therapeutic drugconcentrations systemically. As a result, the subcutaneous tumorresponses observed cannot be explained by systemic gemcitabine exposure.

The age or volume of the subcutaneous tumor at the time of intravesicaltreatment also did not predict the observed subcutaneous tumorresponses. In Group 4, 3 day subcutaneous tumors in animals firsttreated with intravesical gemcitabine continued to grow for several daysprior to arresting. In contrast, 3 day subcutaneous tumors in animalsundergoing a second intravesical gemcitabine treatment in Group 3,immediately declined in tumor volume until the tumors were no longerdetectable.

Without being bound by theory, the study results suggest animmune-mediated effect may have occurred. Gemcitabine intravesicaltreatment of the bladder tumor may have sensitized the animal's immunesystem to the bladder tumor. Upon retreatment of the bladder tumor withintravesical gemcitabine, the previously sensitized or primed immunesystem mounted a stronger and more effective immunological responseresulting in complete eradication of all but one subcutaneous tumor inthe combine Group 3 and 4 tumors.

The current results for the first time show that continuous localtreatment of a bladder tumor with a chemotherapeutic can result in theshrinkage and ultimately ablation of a distant tumor. This suggests thatcontinuous local treatment with chemotherapeutic agents such asgemcitabine can be effective for a treating a wide range of cancersincluding both metastases of the bladder cancer, as well as otherprimary tumors (e.g., breast cancer, colorectal cancer, prostate cancer,or cervical cancer) that metastasize to the bladder.

Example 2

The direct effects of low dose gemcitabine were studied in athymic ratswith human derived MIBC cells, T24-TurboFP635, injected into thebladder. After 3 days tumor growth, gemcitabine or vehicle was perfusedinto the bladder over 5 days, yielding nominal urine concentrations of0, 20, 40, or 80 ug/ml gemcitabine, N=6 per group. Tumor bioluminescencewas measured on day 5. A companion study in immunocompetent ratsinoculated with syngeneic NBTII bladder tumors, provided tumors forimmunocyte analysis.

In the athymic rats with T24 tumors, significant dose dependentreductions in bladder tumor bioluminescence of 47.6%, 70.5% and 91.2% vscontrol were observed in the 20, 40, and 80 ug/ml groups, respectively.Flow cytometric analysis of residual tumors recovered fromimmunocompetent rats with NBTII tumors demonstrated a significantdecrease in the proportion of tumor T regulatory cells to T effectorcells of 85.2%.

Gemcitabine immunogenicity was studied in immunocompetent rats withNBTII cells injected into the bladder and subcutaneous flank tissue;flank tumors were implanted either simultaneously with bladder tumors or14 days after bladder tumor injection. Control groups received onlyflank tumors, N=15, or bladder and flank tumors with vehicle perfusion,N=10. Gemcitabine treatment groups, N=10, received two 5-day bladderperfusions, yielding urine gemcitabine concentrations of 10, 20, and 40ug/ml separated by 7 days.

Flank tumor growth was similar with tumor doubling times of 4.5 daysafter subcutaneous injections of 1.0, 2.5, or 5.0×10⁶ cells. Flank tumorgrowth rates were unchanged in control rats with concomitant bladdertumors and perfused with vehicle. During the first gemcitabine perfusioncycle, flank tumor growth was fully arrested, with tumor sizes averagingonly 50% of controls in rats with concomitant bladder tumors; thiseffect was maintained during the 7-day drug free period in the 60 ug/mlgroup. Initiation of the second perfusion resulted in rapid flank tumorablation in all but one animal completing the study. A similar primingeffect was observed in the 15 and 30 ug/ml groups. Delaying flank tumorimplantation to 3 days before the second perfusion resulted in no tumorgrowth, but immediate tumor ablation.

The current results for the first time show that continuous localtreatment of a bladder tumor with a chemotherapeutic can result in theshrinkage and ultimately ablation of a distant tumor. This suggests thatcontinuous local treatment with chemotherapeutic agents such asgemcitabine can be effective for a treating a wide range of cancersincluding both metastases of the bladder cancer, as well as otherprimary tumors (e.g., breast cancer, colorectal cancer, prostate cancer,or cervical cancer) that metastasize to the bladder.

Example 3

Extending the investigation described in EXAMPLE 1, additional studiesof NBTII bladder and subcutaneous tumors evaluated the effect of varyinggemcitabine bladder exposures with and without simultaneous bladdertumor implantation.

In one set of experiments, gemcitabine perfusion concentrations werevaried to evaluate the effect of differing bladder tumor exposures onsubcutaneous tumor growth rates. Bladder cannulated rats (n=10 pertreatment group) with simultaneously implanted bladder and subcutaneousNBTII tumors were studied over two treatment cycles, each separated by a7-day drug free period, as used in the EXAMPLE 1 study.

Gemcitabine perfusion concentrations of 45 μg/ml and 90 μg/ml weretested, producing nominal urine concentrations of 10 μg/ml and 20 μg/mlrespectively, representing 50% and 75% reductions vs the original studygemcitabine urine concentrations. Subcutaneous tumor growth was measuredduring the study as previously.

As shown in FIG. 6, control subcutaneous tumors grew throughout thestudy period as in the prior example. Gemcitabine, at reduced urineconcentrations, produced a dose related reduction in subcutaneous tumorvolume. Similar to EXAMPLE 1 findings, subcutaneous tumor volume wassignificantly decreased to near ablation during the second treatmentcycle.

Combined these results indicate that lower gemcitabine exposures areable to prime the immune system against subcutaneous NBTII tumors. Thesecond gemcitabine treatment cycle continued to rapidly diminishsubcutaneous tumor volumes despite the reduced gemcitabine urineconcentrations tested.

Example 4

To confirm the observed effects on subcutaneous tumor growth is theresult of the local action of intravesical gemcitabine on bladdertumors, an additional series of experiments were completed in whichbladder cannulated rats were implanted with only subcutaneous NBTIItumors. The animals were then treated with two perfusion cycles ofintravesical gemcitabine as in the previous experiments. As shown inFIG. 7, subcutaneous tumors continued to grow throughout both treatmentcycles and, in both vehicle, and gemcitabine treated bladders. Thesefindings both confirm the presence of a bladder tumor is required andthe observed reductions in subcutaneous tumors are mediatedimmunologically.

Example 5

Rats inoculated with NBTII tumors then administered intravesiculargemcitabine at tumoricidal doses resulted in significant alterations incirculating cytokine levels.

Intravesicular gemcitabine perfusion of 180 ug/ml solution produces anaverage gemcitabine urine concentration of 40 ug/mL which has beendemonstrated to significantly reduce bladder tumor growth afterinoculation with T24 or NBTII tumor cells.

As shown in FIG. 8, after bladder tumor inoculation in rats (n=8) and astumors develop in the bladder, circulating TGF-β plasma concentrationssignificantly increased by day 10 and 15 compared to normal animals(n=3) without tumor inoculation. TGF-β drives Treg cell expression whichin turn suppresses both local and systemic CD4 and CD8 T cell responseagainst the bladder tumor. In contrast, low concentration intravesicalgemcitabine perfusions suppressed TGF-β production and correspondingimmune system inhibition.

Evidence of an adaptive systemic immune response was also observed inrats inoculated with bladder tumor then treated intravesical gemcitabinewhen flow cytometry was performed on the spleens of treated animals.Spleens of animals treated with intravesicular gemcitabine showedincreased IL-10 levels, as shown in FIG. 9. IL-10 increases associatedwith acute treatment are known to facilitate T cell mediated antitumoreffects. TNF-α was also moderately increased upon treatment withgemcitabine, as shown in FIG. 10.

Example 6

Rats were inoculated with NBT-II tumors and the number of activated CD4and CD8 cells in the spleen was assessed by flow cytometry either inrats treated with intravesicular gemcitabine or untreated rats. As shownin FIG. 11, rats that were inoculated with NBT-II tumors and did notreceive intravesicular gemcitabine showed a decrease in activated CD8and CD4 cells. Intravesicular gemcitabine increased the percentage ofactivated CD4 and CD8 cells, thus indicating activation of the immunesystem against the tumor.

The percentage splenic of regulatory T cells was assed using flowcytometry. As shown in FIG. 12, rats that were inoculated with NBT-IItumors and did nto receive intravesicular gemcitabine showed a decreasein both CD4+FOXP3+ and CD8+FOXP3+ regulatory T cells. Intravesiculargemcitabine increased the percentage of activated Cn both CD4+FOXP3+ andCD8+FOXP3+ regulatory T cells, thus indicating activation of thesystemic immune system against the tumor.

1-42. (canceled)
 43. A method of treating tumor metastasis at a sitedistinct from the bladder in an individual having a urothelial carcinomaof lower tract, comprising locally delivering to the bladder aneffective amount of gemcitabine for at least 24 hours.
 44. The method ofclaim 43, wherein the individual has bladder cancer.
 45. The method ofclaim 43, wherein the individual has muscle invasive bladder cancer orcarcinoma in situ (CIS).
 46. The method of claim 43, wherein theindividual is unfit for or refuses cystectomy.
 47. The method of claim43, wherein the individual has not undergone transurethral resection ofbladder tumors (TURBT) prior to intravesical administration ofgemcitbine.
 48. The method of claim 43, wherein the individual hasundergone transurethral resection of bladder tumors (TURBT).
 49. Themethod of claim 43, wherein the individual is unsuitable for systemicchemotherapy.
 50. The method of claim 48, wherein the individual hasresidual tumor at the site of resection.
 51. The method of claim 43,wherein the gemcitabine is delivered continuously to the bladder of theindividual for a period of about seven days to about three weeks. 52.The method of claim 51, wherein the gemcitabine is deliveredcontinuously to the bladder of the individual for a period of aboutseven days to about three weeks at least two times.
 53. The method ofclaim 43, wherein the gemcitabine is delivered continuously to thebladder of the individual for about three weeks.
 54. The method of claim43, wherein the gemcitabine is delivered at a dose of from about 10mg/day to about 50 mg/day.
 55. The method of claim 43, wherein about 100mg to about 200 mg of gemcitabine is delivered to the individual over 21days.
 56. The method of claim 43, wherein the concentration of thegemcitabine in the urine is from about 0.1 μg/mL to about 200 μg/mLduring the delivery period.
 57. The method of claim 56, wherein themethod comprises an induction delivery period followed by a maintenancedelivery period.
 58. The method of claim 43, wherein the metastasis sitethat is distinct from the bladder is selected from the group consistingof liver, lung, bone, brain, lymph node, pelvic node, peritoneum, skin,prostate, breast, colon, rectum, and cervix.
 59. The method of claim 43,wherein the gemcitabine is delivered by an intravesical delivery device.60. The method of claim 59, wherein the intravesical device contains 100mg to 500 mg of gemcitabine.
 61. The method of claim 60, wherein theintravesical device contains 225 mg of gemcitabine.
 62. The method ofclaim 60, wherein the method comprises placing a gemcitabine releasingintravesical device in the bladder of the individual, wherein the deviceremains in the bladder for 21 days, and wherein the gemcitabine iscontinuously delivered to the bladder
 63. The method of claim 60,wherein the intravesical device comprises a housing configured forintravesical insertion; and a dosage form comprising the gemcitabine,wherein the housing holds the dosage form and is configured to releasegemcitabine.
 64. The method of claim 60, wherein the intravesical drugdelivery device comprises a housing which contains and controllablyreleases the gemcitabine and is elastically deformable between aretention shape configured to retain the device in the individual'sbladder and a deployment shape for passage of the device through theindividual's urethra.
 65. The method of claim 51, wherein thegemcitabine is delivered by an intravesical device.
 66. The method ofclaim 65, wherein the intravesical device comprises 225 mg ofgemcitabine.